1
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Chen C, Zou P, Wu X. Development and Validation of an Immune Prognostic Index Related to Infiltration of CD4+ and CD8+ T Cells in Colorectal Cancer. Mol Biotechnol 2025; 67:2758-2773. [PMID: 39026041 DOI: 10.1007/s12033-024-01237-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 06/25/2024] [Indexed: 07/20/2024]
Abstract
Colorectal cancer (CRC) is a highly prevalent cancer worldwide, but treatment outcomes can vary significantly among patients with similar clinical or historical stages. This study aimed to investigate the differences in immune cell abundance associated with malignant progression in CRC patients. We utilized data from patients with CRC obtained from The Cancer Genome Atlas as our training set. To assess immune cell infiltration levels, an immune cell risk score (ICRS) was calculated. Furthermore, we performed network analysis to identify effective T cell-related genes (ETRGs) and subsequently constructed an effective T cell prognostic index (ETPI). The performance of the ETPI was evaluated through external validation using four Gene Expression Omnibus datasets. Additionally, a nomogram analysis and drug sensitivity analysis were conducted to explore the clinical utility of the ETRGs. We also examined the expression of ETRGs in clinical samples. Based on the ICRS, we identified activated CD4+ and CD8+ T cells as protective factors in terms of prognosis. Six ETRGs were identified to develop the ETPI, which exhibited remarkable prognostic performance. In the external validation of immunotherapy, the low ETPI group demonstrated a significantly lower recurrence rate. To optimize therapeutic strategies, we developed a nomogram. Notably, patients with different ETPI values exhibited varying responses to tumor pathway inhibitors. Finally, we observed higher protein expression of certain ETRGs in normal tissues compared to tumors. Our findings suggest that the ETPI may contribute to the precise selection of patients based on tumor microenvironment and key genomic landscape interactions, thereby optimizing drug benefits and informing clinical strategies in future.
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Affiliation(s)
- Chengru Chen
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, 518033, Guangdong Province, China
| | - Peng Zou
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, 518033, Guangdong Province, China
| | - Xiaobin Wu
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, 518033, Guangdong Province, China.
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Tian B, Xia X, Li Q, Qin J. Advances in BRAF mutated colorectal cancer-could deoxycholic acid be the culprit? Biochim Biophys Acta Rev Cancer 2025; 1880:189347. [PMID: 40339670 DOI: 10.1016/j.bbcan.2025.189347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 05/02/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
BRAF mutated colorectal cancer (CRC) often demonstrates distinct molecular profiles characterized by a high methylator phenotype with two different microsatellite statuses (MSI and MSS) and corresponding methylation spectra. Prognostic disparities between these two different BRAF mutated CRC arise from divergent carcinogenic pathways, with BRAF-mutated MSS CRC exhibiting particularly unfavorable clinical outcomes. The underlying mechanism of these phenomena stems from epigenetic heterogeneity in methylation landscapes. Emerging evidences linking cholelithiasis and deoxycholic acid (DCA) to BRAF-mutated CRC pathogenesis warrant systematic investigation into their potential mechanistic relationships. Elucidating these connections could unravel novel pathogenetic pathways and inform targeted strategies for risk mitigation, molecular diagnostics, and therapeutic intervention of BRAF-mutated CRC.
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Affiliation(s)
- Binle Tian
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Xin Xia
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Qi Li
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
| | - Jian Qin
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
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3
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Pizzamiglio M, Soulabaille A, Lahlou W, Pilla L, Zaanan A, Taieb J. Advances and challenges in targeted therapies for HER2-amplified colorectal cancer. Eur J Cancer 2025; 222:115471. [PMID: 40311507 DOI: 10.1016/j.ejca.2025.115471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/16/2025] [Accepted: 04/18/2025] [Indexed: 05/03/2025]
Abstract
Colorectal cancer is the third most common cancer in terms of incidence rate in adults and the second most common cause of cancer-related death in Europe. Despite an increase in overall survival throughout the years, the prognosis of metastatic colorectal cancer remains poor. Until recently, its treatment was based on the use of standard chemotherapy combined with, anti-epidermal growth factor receptor (for RAS wild-type tumors) or anti-vascular endothelial growth factor, or immunotherapy for tumors with mismatch repair deficiency. Over the last years, precision medicine has become a challenge in oncology and there has been an increasing development of biomarker-driven therapies for metastatic colorectal cancer leading to better outcomes for specific molecular subgroups of patients. Human epidermal growth factor receptor 2 (HER2) amplification/overexpression has been identified in about 6 % of patients with RAS wild-type metastatic CRC and established as an important and drugable biomarker. Its prognostic and predictive implications are still debated but HER2 becoming a therapeutic target with promising results of anti-HER2 therapies for HER2-positive metastatic CRC. Multiple HER2-targeted regimens are now part of National Comprehensive Cancer Network and European Society for Medical Oncology guidelines with two recent Food and Drug Administration approvals for previously treated HER2-positive metastatic colorectal cancer for tucatinib (in combination with trastuzumab) and for trastuzumab-deruxtecan in patients with previously treated HER2-positive metastatic colorectal cancer. This review explores the prognostic and predictive value of HER2 as a biomarker in CRC, describing its molecular structure, the clinical characteristics of patients with HER2 alterations, diagnostic approaches and the most relevant clinical trials assessing its current and future role as a therapeutic target in metastatic colorectal cancer.
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Affiliation(s)
- Margot Pizzamiglio
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France
| | - Audrey Soulabaille
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France
| | - Widad Lahlou
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France
| | - Lorenzo Pilla
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France
| | - Aziz Zaanan
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France
| | - Julien Taieb
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France.
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4
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Dash P, Yadav V, Das B, Satapathy SR. Experimental toolkit to study the oncogenic role of WNT signaling in colorectal cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189354. [PMID: 40414319 DOI: 10.1016/j.bbcan.2025.189354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 05/19/2025] [Accepted: 05/19/2025] [Indexed: 05/27/2025]
Abstract
Colorectal cancer (CRC) is linked to the WNT/β-catenin signaling as its primary driver. Aberrant activation of WNT/β-catenin signaling is closely correlated with increased incidence, malignancy, poorer prognosis, and even higher cancer-related death. Research over the years has postulated various experimental models that have facilitated an understanding of the complex mechanisms underlying WNT signaling in CRC. In the present review, we have comprehensively summarized the in vitro, in vivo, patient-derived, and computational models used to study the role of WNT signaling in CRC. We discuss the use of CRC cell lines and organoids in capturing the molecular intricacies of WNT signaling and implementing xenograft and genetically engineered mouse models to mimic the tumor microenvironment. Patient-derived models, including xenografts and organoids, provide valuable insights into personalized medicine approaches. Additionally, we elaborated on the role of computational models in simulating WNT signaling dynamics and predicting therapeutic outcomes. By evaluating the advantages and limitations of each model, this review highlights the critical contributions of these systems to our understanding of WNT signaling in CRC. We emphasize the need to integrate diverse model systems to enhance translational research and clinical applications, which is the primary goal of this review.
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Affiliation(s)
- Pujarini Dash
- Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Vikas Yadav
- Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Biswajit Das
- Department of Molecular Cell and Developmental Biology, University of California, Santa Cruz, USA
| | - Shakti Ranjan Satapathy
- Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Skåne University Hospital, Lund University, Malmö, Sweden
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Matejcic M, Teer JK, Hoehn HJ, Diaz DB, Shankar K, Gong J, Nguyen NT, Loroña NC, Coppola D, Fulmer CG, Saglam O, Jiang K, Cress WD, Muñoz-Antonia T, Flores I, Gordián ER, Oliveras Torres JA, Felder SI, Sanchez J, Fleming JB, Siegel EM, Freedman JA, Dutil J, Stern MC, Fridley BL, Figueiredo JC, Schmit SL. Colorectal Tumors in Diverse Patient Populations Feature a Spectrum of Somatic Mutational Profiles. Cancer Res 2025; 85:1928-1944. [PMID: 40126181 DOI: 10.1158/0008-5472.can-24-0747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 08/21/2024] [Accepted: 02/25/2025] [Indexed: 03/25/2025]
Abstract
Admixed populations, including the Hispanic/Latino/a community, are underrepresented in cancer genetic/genomic studies. Leveraging the Latino Colorectal Cancer Consortium (LC3) and other existing datasets, we analyzed whole-exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer to map somatic mutational features by ethnicity and genetic similarity. Global proportions of African, Asian, European, and Native American genetic ancestries were estimated using ADMIXTURE. Associations between these proportions and somatic mutational features were examined using logistic regression. APC, TP53, and KRAS were the top three mutated genes across all participants and in the subset of Latino individuals in LC3. In analyses examining recurrently mutated genes, tumors from patients of Latino ethnicity had fewer KRAS and PIK3CA mutations compared with tumors from non-Latino patients. Genetic ancestry overall was associated with CDC27 mutation status, and African genetic ancestry was associated with SMAD2 mutation status. In exome-wide analyses, African genetic ancestry was significantly associated with higher odds of mutation in KNCN and TMEM184B. Native American genetic ancestry was associated with a lower frequency of microsatellite instability-high tumors. The SBS11 mutational signature was associated with Native American genetic ancestry as well as Latino ethnicity. In an independent replication dataset, MSK-IMPACT, estimates of association were largely consistent in direction but nonsignificant. A meta-analysis of LC3 and MSK-IMPACT showed that African genetic ancestry was significantly associated with KRAS mutation status and MSI status. This work facilitates precision medicine initiatives by providing insights into the contribution of genetic ancestry to molecular features of colorectal tumors. Significance: Analysis of tumors from various populations can broadly characterize genomic landscapes and enhance precision medicine strategies.
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Affiliation(s)
- Marco Matejcic
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jamie K Teer
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Hannah J Hoehn
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Non-Therapeutic Research Office, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Diana B Diaz
- Non-Therapeutic Research Office, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Kritika Shankar
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio
| | - Jun Gong
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Nathalie T Nguyen
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Nicole C Loroña
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Domenico Coppola
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Clifton G Fulmer
- Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Ozlen Saglam
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Kun Jiang
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - W Douglas Cress
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Teresita Muñoz-Antonia
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Idhaliz Flores
- Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University, Ponce, Puerto Rico
| | - Edna R Gordián
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - José A Oliveras Torres
- Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University, Ponce, Puerto Rico
| | - Seth I Felder
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Julian Sanchez
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Erin M Siegel
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Non-Therapeutic Research Office, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jennifer A Freedman
- Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Duke Cancer Institute, Durham, North Carolina
| | - Julie Dutil
- Division of Clinical and Translational Cancer Research, Comprehensive Cancer Center of the University of Puerto Rico, San Juan, Puerto Rico
| | - Mariana C Stern
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California
| | - Brooke L Fridley
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Stephanie L Schmit
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, Ohio
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6
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Appleyard JW, Williams CJM, Manca P, Pietrantonio F, Seligmann JF. Targeting the MAP kinase pathway in colorectal cancer: A journey in personalized medicine. Clin Cancer Res 2025:762187. [PMID: 40310309 PMCID: PMC7617663 DOI: 10.1158/1078-0432.ccr-25-0107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/25/2025] [Accepted: 04/09/2025] [Indexed: 05/02/2025]
Abstract
The anti-EGFR agents, cetuximab and panitumumab, were the first targeted agents to be licensed in colorectal cancer and marked a significant advancement in personalized care. Initial biomarkers provided poor discrimination between responders and non-responders. Through hypothesis-led translational studies, tumor genomic negative predictive markers were identified, and treatment is now limited to patients with RAS and BRAF wild-type disease. Guidelines further recommend treatment limitation to those with left-primary tumor location (PTL). Despite such progress, anti-EGFR response remains variable within the biomarker-selected population, indicating the presence of additional mechanisms of resistance and underscoring the need for novel positive predictive biomarkers, and novel targeted agents. This review explores established and emerging predictive biomarkers of anti-EGFR efficacy, including tumor genetic alterations beyond RAS and BRAF, as well as the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG). To date, biomarker discovery and validation have largely been performed within post hoc analyses of existing clinical trial datasets. We highlight ongoing prospective clinical trials aiming to validate earlier findings and describe how novel biomarkers are being used to re-evaluate anti-EGFR agents in treatment settings where earlier trials, among non-biomarker selected populations, yielded negative results - including right-PTL, locally advanced disease, and anti-EGFR rechallenge strategies. Additionally, we discuss how our improved understanding of the molecular mechanisms underpinning anti-EGFR response and resistance is being leveraged to develop novel targeted agents.
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Affiliation(s)
- Jordan W. Appleyard
- Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds, United Kingdom
| | | | - Paolo Manca
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Jenny F. Seligmann
- Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds, United Kingdom
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Fatfat Z, Hussein M, Fatfat M, Gali-Muhtasib H. Omics technologies as powerful approaches to unravel colorectal cancer complexity and improve its management. Mol Cells 2025; 48:100200. [PMID: 40024318 PMCID: PMC11976254 DOI: 10.1016/j.mocell.2025.100200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/31/2025] [Accepted: 02/22/2025] [Indexed: 03/04/2025] Open
Abstract
Colorectal cancer (CRC) continues to rank among the deadliest and most prevalent cancers worldwide, necessitating an innovative and comprehensive approach that addresses this serious health challenge at various stages, from screening and diagnosis to treatment and prognosis. As CRC research progresses, the adoption of an omics-centered approach holds transformative potential to revolutionize the management of this disease. Advances in omics technologies encompassing genomics, transcriptomics, proteomics, metabolomics, and epigenomics allow to unravel the oncogenic alterations at these levels, elucidating the intricacies and the heterogeneous nature of CRC. By providing a comprehensive molecular landscape of CRC, omics technologies enable the discovery of potential biomarkers for early non-invasive detection of CRC, definition of CRC subtypes, prediction of its staging, prognosis, and overall survival of CRC patients. They also allow the identification of potential therapeutic targets, prediction of drug response, tracking treatment efficacy, detection of residual disease and cancer relapse, and deciphering the mechanisms of drug resistance. Moreover, they allow the distinction of non-metastatic CRC patients from metastatic ones as well as the stratification of metastatic risk. Importantly, omics technologies open up new opportunities to establish molecular-based criteria to guide the selection of effective treatment paving the way for the personalization of therapy for CRC patients. This review consolidates current knowledge on the omics-based preclinical discoveries in CRC research emphasizing the significant potential of these technologies to improve CRC screening, diagnosis, and prognosis and promote the implementation of personalized medicine to ultimately reduce CRC prevalence and mortality.
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Affiliation(s)
- Zaynab Fatfat
- Department of Biology, American University of Beirut, Beirut, Lebanon
| | - Marwa Hussein
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon
| | - Maamoun Fatfat
- Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon
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8
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Villacorta R, Gallagher-Colombo S, Lahiji A, Myers S, Briggs J, Phalguni A. Systematic literature review of the epidemiology of neurotrophic tyrosine receptor kinase positive solid tumor sites. Future Oncol 2025; 21:1403-1415. [PMID: 40152538 PMCID: PMC12051583 DOI: 10.1080/14796694.2025.2481022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 03/14/2025] [Indexed: 03/29/2025] Open
Abstract
AIMS This study aimed to expand on existing systematic literature reviews (SLRs) by assessing the prevalence of neurotrophic tyrosine receptor kinase (NTRK) fusion-positive mutations across solid tumors in adult U.S populations. It further evaluated incidence, testing, treatment, mortality, and progression rates by tumor type, extending evidence through 2023. MATERIALS & METHODS A SLR was conducted following Cochrane and PRISMA guidelines, with searches across Ovid Embase, Ovid MEDLINE, and Cochrane Library databases for studies published from 2013 to August 2023. Eligibility criteria included studies on NTRK fusion-positive tumors in patients aged ≥12 years. Data were extracted and assessed using the Newcastle-Ottawa Scale and JBI checklist. RESULTS This SLR identified 160 studies, reporting NTRK fusion prevalence ranging from 0.03% to 0.70% across solid tumors. TRK inhibitors, particularly larotrectinib and entrectinib, were commonly used treatments. Prevalence varied significantly by cancer type, being higher in rarer cancers, such as papillary thyroid carcinoma (up to 21.4%). CONCLUSIONS NTRK fusions are rare, with wide prevalence variability among cancer types. The findings highlight the need for standardized diagnostic methods and larger real-world studies to improve prevalence estimates and assess the impact of NTRK fusions on outcomes, ultimately aiding in the optimization of targeted treatments for affected patients.
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Affiliation(s)
| | | | | | - Sky Myers
- Genesis Research Group, Hoboken, NJ, USA
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Li Q, Lv J, Duan H, Sun P, Lu B, Shi W, Cai Y. KCNC3 as a prognostic indicator and a predictive marker for immunotherapy in colorectal cancer. J Gastrointest Oncol 2025; 16:453-469. [PMID: 40386598 PMCID: PMC12078811 DOI: 10.21037/jgo-24-718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 03/31/2025] [Indexed: 05/20/2025] Open
Abstract
Background Colorectal cancer (CRC) is a heterogeneous disease that is associated with several genetic or somatic mutations. Cancer immunotherapy has become a novel and revolutionary method of treatment for patients with advanced tumors. However, effective biomarkers that can reflect the response of CRC patients to immunotherapy have still not been identified. Our study aimed to explore the expression and functional role of KCNC3 in CRC. Methods The correlation between KCNC3 expression levels and CRC progression was explored and validated using data from The Cancer Genome Atlas (TCGA) and patient's samples from the Affiliated Hospital of Nantong University. Univariate and multivariate Cox regression models were developed to determine the predictive value of KCNC3 on the prognosis and immune activation of patients with CRC. We predicted the immunotherapy response in both the high and low KCNC3 expression subgroups. Finally, we confirmed that KCNC3 promotes the proliferation and invasion of colon cancer cells. Results In this study, data from TCGA database and clinical patient parameters showed that high KCNC3 expression was associated with tumor immune infiltration and poor prognosis of CRC. KCNC3 expression was positively correlated with the infiltration levels of CD4+ cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), which contributed to the formation of an immunosuppressive tumor microenvironment (TME). The high expression of KCNC3 was accompanied by the upregulation of immune checkpoint molecules, including PDCD1, LAG3, FOXP3, and CTLA4, which stimulated tumor cells to evade immune surveillance. In vitro experiment, KCNC3 knockdown inhibited the growth and metastasis of SW1116 cells. Conclusions This study demonstrated that the high expression of KCNC3 contributes to the growth and invasion of CRC and confers with immunosuppressive microenvironment that can promote tumor progression and can be used to predict the poor clinical outcome of CRC patients.
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Affiliation(s)
- Quanqing Li
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jiaying Lv
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Hongxia Duan
- Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong, China
| | - Pingping Sun
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Bing Lu
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Wenyu Shi
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China
- Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong, China
| | - Yihong Cai
- Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong, China
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Chen WJ, Wang HW, Wang LJ, Xu D, Liu M, Xing BC. Mutational status of RAS, SMAD4 and APC predicts survival after resection of colorectal liver metastases in Chinese patients: prognostic stratification based on genetic sequencing data of multiple somatic genes. World J Surg Oncol 2025; 23:172. [PMID: 40301949 PMCID: PMC12042571 DOI: 10.1186/s12957-025-03755-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 03/14/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND This study aimed to investigate the impact of the mutational status of multiple genes on survival in Chinese patients with colorectal liver metastases (CRLM) undergoing liver resection. METHODS This study included 519 Chinese patients undergoing curative liver resection for CRLM between 2011 and 2021 and had genomic sequencing data of 620 genes available for analysis. The genes associated with overall survival (OS) were identified using Cox regression analyses. The patients were stratified according to a novel scoring system based on the number of genes with a deleterious status (mutation or wild type), and OS was compared among the groups. The prognostic capacity of the scoring system was assessed using Harrell's C-index. RESULTS Twelve genes were mutated in more than 10% of the patients. RAS mutation, SMAD4 mutation, and APC wild-type status were significantly associated with worse OS. A scoring system was built based on the mutational status of RAS, SMAD4, and APC. Higher scores were significantly associated with worse OS (HR > 1, p < 0.05, for any two groups), and the patients with a score of 3 had poor survival with a median OS of only 17.1 months. The scoring system demonstrated moderate discriminative capacity (Harrell's C-index = 0.627). CONCLUSIONS In Chinese patients, the mutational status of RAS, SMAD4, and APC was significantly associated with survival after CRLM resection. The three-gene scoring system provided information on prognostic stratification for survival, which can be used to improve precision surgery for CRLM.
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Affiliation(s)
- Wen-Jia Chen
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Hong-Wei Wang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Li-Jun Wang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Da Xu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Ming Liu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
| | - Bao-Cai Xing
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-biliary-pancreatic Surgery I, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
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Zhang X, Zhang P, Dong H, Li L, Lu L, Lv H, Yu X, Yu H. Homologous Recombination Deficiency Is Associated with Shorter Survival in Colorectal Cancer Patients. J Gastrointest Cancer 2025; 56:105. [PMID: 40261491 DOI: 10.1007/s12029-025-01231-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2025] [Indexed: 04/24/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) patients benefit more from immune checkpoint inhibitor therapy, but they only account for around 15% of all patients. The remaining patients still lack effective therapeutic biomarkers to predict their prognosis. METHODS We performed whole-exome sequencing (WES) to analyze 84 CRC specimens, classifying them into different groups based on their microsatellite status (MS), tumor mutation burden (TMB), homologous recombination deficiency (HRD) score, and clinicopathological features, which might be associated with clinical outcomes. Survival analysis and multivariable Cox regression modeling were employed to identify prognostic indicators. Comparative genomic profiling evaluated somatic mutations, copy number variations (CNVs), and pathway activation patterns across clinical subgroups. RESULTS The characteristics of the cohort (N = 84) revealed a median age of 52 years, with a male predominance (61.9%) and a majority of patients presenting with stage IV disease (77%). The HRD-high (HRD-H) subgroup accounted for 16.7%, while 19.0% of cases were microsatellite instability-high (MSI-H) and 22.6% were TMB-high (TMB-H). Multivariable analysis identified HRD-H as an independent predictor of overall survival (OS: HR = 0.19, 95% CI 0.12-0.94, p = 0.002). Comparative genomics demonstrated distinct mutation landscapes between HRD-H and HRD-low subgroups. In microsatellite-stable (MSS) patients, HRD-H status correlated with enriched SMAD4 mutations (p < 0.01) and differential activation of TGF-β/MYC signaling pathways compared to HRD-H-MSI counterparts. CONCLUSION HRD status serves as a novel independent prognostic biomarker in CRC. Our multi-parametric genomic framework delineates stratification-specific molecular signatures, advocating for HRD-integrated molecular diagnostics to optimize CRC management.
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Affiliation(s)
- Xuan Zhang
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, School of Medicine, Sir Runrun Shaw Hospital, Zhejiang University, Zhejiang, 310016, P.R. China
- Zhejiang Provincial Key Laboratory of Digital Medical Diagnostic Technology, DiAn Diagnostic Group Co., Ltd. Hangzhou 310020, Zhejiang, P.R. China
| | - Pan Zhang
- Department of Clinical Laboratory, Gongli Hospital of Shanghai Pudong New Area, 219 Miao Pu Road, Shanghai, 200135, China
| | - Hua Dong
- Zhejiang Provincial Key Laboratory of Digital Medical Diagnostic Technology, DiAn Diagnostic Group Co., Ltd. Hangzhou 310020, Zhejiang, P.R. China
| | - Lin Li
- Zhejiang Provincial Key Laboratory of Digital Medical Diagnostic Technology, DiAn Diagnostic Group Co., Ltd. Hangzhou 310020, Zhejiang, P.R. China
| | - Lingling Lu
- Zhejiang Provincial Key Laboratory of Digital Medical Diagnostic Technology, DiAn Diagnostic Group Co., Ltd. Hangzhou 310020, Zhejiang, P.R. China
| | - Hongyuan Lv
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, School of Medicine, Sir Runrun Shaw Hospital, Zhejiang University, Zhejiang, 310016, P.R. China
| | - Xin Yu
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, School of Medicine, Sir Runrun Shaw Hospital, Zhejiang University, Zhejiang, 310016, P.R. China.
| | - Hong Yu
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, School of Medicine, Sir Runrun Shaw Hospital, Zhejiang University, Zhejiang, 310016, P.R. China.
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12
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Shin AE, Sugiura K, Kariuki SW, Cohen DA, Flashner SP, Klein-Szanto AJ, Nishiwaki N, De D, Vasan N, Gabre JT, Lengner CJ, Sims PA, Rustgi AK. LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models. J Clin Invest 2025; 135:e186035. [PMID: 39808497 PMCID: PMC11996871 DOI: 10.1172/jci186035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer death because of metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present a comprehensive analysis of vertical inhibition of the PI3K/AKT pathway in CRC using the FDA-approved drugs alpelisib and capivasertib (an AKT inhibitor) in combination with LY2584702 (a ribosomal protein S6 kinase inhibitor) in CRC cell lines and mouse- and patient-derived organoids. Tissue microarrays from patients with CRC verified that LIN28B and PI3K/AKT pathway activation correlate with CRC progression. These findings highlight the critical role of the LIN28B-mediated PI3K/AKT pathway in CRC metastasis, the therapeutic potential of targeted inhibition, and the promise of patient-derived organoids in precision medicine in metastatic CRC.
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Affiliation(s)
- Alice E. Shin
- Division of Digestive and Liver Diseases, Department of Medicine, and
| | - Kensuke Sugiura
- Division of Digestive and Liver Diseases, Department of Medicine, and
| | | | - David A. Cohen
- Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons; Columbia University Irving Medical Center, New York, New York, USA
| | | | | | | | - Dechokyab De
- Division of Digestive and Liver Diseases, Department of Medicine, and
| | - Neil Vasan
- Division of Hematology and Oncology, Department of Medicine, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
| | - Joel T. Gabre
- Division of Digestive and Liver Diseases, Department of Medicine, and
| | - Christopher J. Lengner
- Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Peter A. Sims
- Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
| | - Anil K. Rustgi
- Division of Digestive and Liver Diseases, Department of Medicine, and
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13
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Chia S, Wen Seow JJ, Peres da Silva R, Suphavilai C, Shirgaonkar N, Murata-Hori M, Zhang X, Yong EY, Pan J, Thangavelu MT, Periyasamy G, Yap A, Anand P, Muliaditan D, Chan YS, Siyu W, Yong CW, Hong N, Ran G, Sim NL, Guo YA, Yi Teh AX, Wei Ling CC, Wei Tan EK, Pei Cherylin FW, Chang M, Han S, Seow-En I, Chen Hui LR, Hsia Gan AH, Yap CK, Ng HH, Skanderup AJ, Chinswangwatanakul V, Riansuwan W, Trakarnsanga A, Pithukpakorn M, Tanjak P, Chaiboonchoe A, Park D, Kim DK, Iyer NG, Tsantoulis P, Tejpar S, Kim JE, Kim TI, Sampattavanich S, Tan IB, Nagarajan N, DasGupta R. CAN-Scan: A multi-omic phenotype-driven precision oncology platform identifies prognostic biomarkers of therapy response for colorectal cancer. Cell Rep Med 2025; 6:102053. [PMID: 40187357 PMCID: PMC12047494 DOI: 10.1016/j.xcrm.2025.102053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 12/10/2024] [Accepted: 03/10/2025] [Indexed: 04/07/2025]
Abstract
Application of machine learning (ML) on cancer-specific pharmacogenomic datasets shows immense promise for identifying predictive response biomarkers to enable personalized treatment. We introduce CAN-Scan, a precision oncology platform, which applies ML on next-generation pharmacogenomic datasets generated from a freeze-viable biobank of patient-derived primary cell lines (PDCs). These PDCs are screened against 84 Food and Drug Administration (FDA)-approved drugs at clinically relevant doses (Cmax), focusing on colorectal cancer (CRC) as a model system. CAN-Scan uncovers prognostic biomarkers and alternative treatment strategies, particularly for patients unresponsive to first-line chemotherapy. Specifically, it identifies gene expression signatures linked to resistance against 5-fluorouracil (5-FU)-based drugs and a focal copy-number gain on chromosome 7q, harboring critical resistance-associated genes. CAN-Scan-derived response signatures accurately predict clinical outcomes across four independent, ethnically diverse CRC cohorts. Notably, drug-specific ML models reveal regorafenib and vemurafenib as alternative treatments for BRAF-expressing, 5-FU-insensitive CRC. Altogether, this approach demonstrates significant potential in improving biomarker discovery and guiding personalized treatments.
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Affiliation(s)
- Shumei Chia
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore.
| | - Justine Jia Wen Seow
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Rafael Peres da Silva
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Chayaporn Suphavilai
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Niranjan Shirgaonkar
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Maki Murata-Hori
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Xiaoqian Zhang
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Elena Yaqing Yong
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Jiajia Pan
- National Cancer Centre, Singapore, Singapore
| | - Matan Thangavelu Thangavelu
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Experimental Drug Development Centre (EDDC), A∗STAR, Singapore, Singapore
| | - Giridharan Periyasamy
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Experimental Drug Development Centre (EDDC), A∗STAR, Singapore, Singapore
| | - Aixin Yap
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Padmaja Anand
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Daniel Muliaditan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Yun Shen Chan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong, China
| | - Wang Siyu
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Chua Wei Yong
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Nguyen Hong
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Gao Ran
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Ngak Leng Sim
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Yu Amanda Guo
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | | | | | - Emile Kwong Wei Tan
- Department of Colorectal Surgery, Singapore General Hospital, Singapore, Singapore
| | - Fu Wan Pei Cherylin
- Department of Colorectal Surgery, Singapore General Hospital, Singapore, Singapore
| | - Meihuan Chang
- Department of Colorectal Surgery, Singapore General Hospital, Singapore, Singapore
| | - Shuting Han
- National Cancer Centre, Singapore, Singapore
| | - Isaac Seow-En
- Department of Colorectal Surgery, Singapore General Hospital, Singapore, Singapore
| | | | - Anna Hwee Hsia Gan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Choon Kong Yap
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Huck Hui Ng
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Anders Jacobsen Skanderup
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Vitoon Chinswangwatanakul
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Siriraj Cancer Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Woramin Riansuwan
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Atthaphorn Trakarnsanga
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Manop Pithukpakorn
- Siriraj Genomics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol, Bangkok, Thailand
| | - Pariyada Tanjak
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Siriraj Cancer Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Amphun Chaiboonchoe
- Siriraj Center of Research Excellence for Precision Medicine and Systems Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Daye Park
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Dong Keon Kim
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | | | - Petros Tsantoulis
- Hôpitaux Universitaires de Genève, University of Geneva, Geneva, Switzerland
| | - Sabine Tejpar
- Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Jung Eun Kim
- R&D center PODO Therapeutics Co. 338 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13493, Republic of Korea
| | - Tae Il Kim
- R&D center PODO Therapeutics Co. 338 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13493, Republic of Korea; Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Somponnat Sampattavanich
- Siriraj Center of Research Excellence for Precision Medicine and Systems Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Iain Beehuat Tan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; National Cancer Centre, Singapore, Singapore; Duke-National University of Singapore Medical School, Singapore, Singapore.
| | - Niranjan Nagarajan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Ramanuj DasGupta
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; CRUK Scotland Institute, School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
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14
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Lin Y, Lau HCH, Liu C, Ding X, Sun Y, Rong J, Zhang X, Wang L, Yuan K, Miao Y, Wu WKK, Wong SH, Sung JJY, Yu J. Multi-cohort analysis reveals colorectal cancer tumor location-associated fecal microbiota and their clinical impact. Cell Host Microbe 2025; 33:589-601.e3. [PMID: 40209677 DOI: 10.1016/j.chom.2025.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 02/12/2025] [Accepted: 03/11/2025] [Indexed: 04/12/2025]
Abstract
Microbial alterations in different tumor locations of colorectal cancer (CRC) remain unclear. Here, 1,375 fecal metagenomes from six in-house and published datasets were analyzed, including 128 right-sided CRC (rCRC), 168 left-sided CRC (lCRC), 250 rectal cancer (RC), and 829 controls. Firmicutes progressively increase from rCRC, lCRC, to RC, in contrast to the gradual decrease of Bacteroidetes. Tumor location-associated fecal microbes are identified, including Veillonella parvula for rCRC, Streptococcus angionosus for lCRC, and Peptostreptococcus anaerobius for RC, while Fusobacterium nucleatum is enriched in all tumor locations. Tumor location-associated bacteria correlate with patient survival. Clinically, we establish a microbial biomarker panel for each tumor location that accurately diagnoses rCRC (area under the receiver operating characteristic curve [AUC] = 91.59%), lCRC (AUC = 91.69%), or RC (AUC = 90.53%) from controls. Tumor location-specific biomarkers also have higher diagnostic accuracy (AUC = 91.38%) than location-non-specific biomarkers (AUC = 82.92%). Overall, we characterize fecal microbes associated with different CRC tumor locations, highlighting that tumor location should be considered in non-invasive diagnosis.
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Affiliation(s)
- Yufeng Lin
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Harry Cheuk-Hay Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chuanfa Liu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiao Ding
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yang Sun
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Disease, Yunnan Geriatric Medical Center, Kunming, Yunnan, China
| | - Jiamei Rong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Disease, Yunnan Geriatric Medical Center, Kunming, Yunnan, China
| | - Xiang Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Luyao Wang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Kai Yuan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yinglei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Disease, Yunnan Geriatric Medical Center, Kunming, Yunnan, China
| | - William Ka-Kei Wu
- Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Sunny Hei Wong
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Joseph Jao-Yiu Sung
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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15
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Schulze M, Wang X, Hamad J, Quintanilha JCF, Pasquina LW, Hopkins JF, Scheuenpflug J, Feng Z. Real-world genomic landscape of colon and rectal cancer. FEBS Open Bio 2025; 15:674-685. [PMID: 39865537 PMCID: PMC11961397 DOI: 10.1002/2211-5463.13957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 11/15/2024] [Accepted: 12/10/2024] [Indexed: 01/28/2025] Open
Abstract
MAPK signaling activation is an important driver event in colorectal cancer (CRC) tumorigenesis that informs therapy selection, but detection by liquid biopsy can be challenging. We analyze real-world comprehensive genomic profiling (CGP) data to explore the landscape of alterations in BRAF or RAS in CRC patients (N = 51 982) and co-occurrence with other biomarkers. A pathogenic RAS or BRAF alteration was found in 63.2% and 57.9% of colon and rectal cancer samples, respectively. In a subset of 140 patients with both tissue- and liquid-based CGP, the sensitivity of liquid for results found by tissue was 100% when ctDNA tumor fraction was at least 1%, illustrating the utility of tissue and liquid biopsy in detecting driver alterations in CRC.
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Affiliation(s)
- Markus Schulze
- Clinical Measurement Sciences, Global Research & DevelopmentMerck KGaADarmstadtGermany
| | - XiaoZhe Wang
- Clinical Measurement Sciences, Global Research & DevelopmentEMD SeronoBillericaMAUSA
| | - Jawad Hamad
- Medical Unit OncologyMerck Healthcare KGaADarmstadtGermany
| | | | | | | | - Juergen Scheuenpflug
- Clinical Measurement Sciences, Global Research & DevelopmentMerck KGaADarmstadtGermany
| | - Zheng Feng
- Clinical Measurement Sciences, Global Research & DevelopmentEMD SeronoBillericaMAUSA
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16
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Boscolo Bielo L, Crimini E, Repetto M, Barberis M, Battaiotto E, Katrini J, Martino E, Gaudio G, Lombardi M, Zanzottera C, Aurilio G, Belli C, Zhan Y, Fuorivia V, Marsicano RM, Etessami JD, Zagami P, Marra A, Trapani D, Taurelli Salimbeni B, Criscitiello C, Ciardiello D, Lavinia B, Gervaso L, Cella CA, Spada F, Zampino MG, Fusco N, Fazio N, Guerini Rocco E, Curigliano G. Molecular tumour board in gastrointestinal cancers. ESMO Open 2025; 10:104510. [PMID: 40112698 PMCID: PMC11979463 DOI: 10.1016/j.esmoop.2025.104510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/16/2025] [Accepted: 02/17/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Comprehensive genomic profiling (CGP) is being increasingly adopted in clinical practice to guide the use of molecularly guided treatment options (MGTOs). To optimize the integration of MGTOs in routine cancer care, molecular tumour boards (MTBs) have been established. Limited data are available to address the clinical value of implementing MTBs to inform treatment decision making in patients with gastrointestinal (GI) cancers. MATERIALS AND METHODS We retrospectively retrieved medical records from patients with advanced GI cancers discussed at the European Institute of Oncology's MTB between August 2019 and December 2024. We evaluated clinical outcomes resulting from applying MGTOs in cancer care according to MTB recommendations, describing real-world progression-free (rwPFS) and overall survival (OS), and used the growth modulation index (GMI) (ratio of PFSMTB to PFSprior) to quantify the effectiveness of MTB's recommended cancer treatment in extending PFS. RESULTS Among 192 patients with GI cancers discussed at MTB, 139 (72.3%) received an MTB treatment recommendation. For patients with available follow-up data (n = 82), 31 patients (41.4%, 17.7% overall) received MGTOs, while 51 patients received standard treatments. Patients receiving MGTOs exhibited a longer rwPFS compared with cases receiving standard therapies [5.35 versus 3.55 months, hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.36-1.08, P = 0.08] and with unmatched cases showing actionable biomarkers but not treated with targeted agents (n = 31) (rwPFS 5.35 versus 2.40 months, HR 0.49, 95% CI 0.27-0.90, P = 0.02). The use of MGTOs resulted in a GMI of 1.12 (interquartile range 0.68-2.36). The European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) tier I-III treatments resulted in a restricted mean PFS gain of 4.87 months compared with standard therapies (95% CI 1.02-8.72 months, P = 0.01). No OS difference was observed between patients receiving MGTOs and standard treatments (P = 0.89). CONCLUSIONS Our results suggest that MTB-informed clinical decision making could provide valuable clinical benefits and expanded therapeutic options in patients affected by advanced GI cancers.
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Affiliation(s)
- L Boscolo Bielo
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
| | - E Crimini
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
| | - M Repetto
- Early Drug Development Service, Memorial Sloan-Kettering Cancer Center, New York, USA
| | - M Barberis
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - E Battaiotto
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
| | - J Katrini
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
| | - E Martino
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - G Gaudio
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - M Lombardi
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - C Zanzottera
- Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - G Aurilio
- Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - C Belli
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Y Zhan
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - V Fuorivia
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
| | - R M Marsicano
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
| | - J D Etessami
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
| | - P Zagami
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - A Marra
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - D Trapani
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
| | - B Taurelli Salimbeni
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - C Criscitiello
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
| | - D Ciardiello
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - B Lavinia
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - L Gervaso
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - C A Cella
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - F Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - M G Zampino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - N Fusco
- Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy; Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - N Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - E Guerini Rocco
- Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy; Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - G Curigliano
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy.
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17
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Dexheimer TS, Davoudi Z, Coussens NP, Silvers T, Morris J, Takebe N, Said R, Moscow JA, Doroshow JH, Teicher BA. Combinatorial screen of targeted agents with the PI3K inhibitors inavolisib, alpelisib, duvelisib, and copanlisib in multi-cell type tumor spheroids. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2025; 32:100222. [PMID: 39999911 PMCID: PMC12034487 DOI: 10.1016/j.slasd.2025.100222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/05/2025] [Accepted: 02/22/2025] [Indexed: 02/27/2025]
Abstract
Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is a key contributor to cancer, making PI3K inhibitors a promising approach for targeted therapy. The selectivity of available inhibitors varies across different PI3K isoforms. Alpelisib and inavolisib are selective for the α-isoform, while duvelisib targets the δ- and γ-isoforms, and copanlisib is a pan-PI3K inhibitor, active against all isoforms. This study investigated the activity of these four PI3K inhibitors in combination with other targeted agents using multi-cell type tumor spheroids composed of 60% malignant cells, 25% endothelial cells, and 15% mesenchymal stem cells. Twenty-nine tumor spheroid models were evaluated, including twenty-six patient-derived cancer cell lines from the NCI Patient-Derived Models Repository and three established cell lines from the NCI-60 human tumor cell line panel. Additive and/or synergistic effects were observed with alpelisib or inavolisib or copanlisib in combination with a RAS/MEK/ERK pathway inhibitor, either selumetinib (MEK), ravoxertinib (ERK 1/2), or tovorafenib (DAY101, RAF). Combinations of each of these three PI3K inhibitors with the KRAS mutation specific inhibitors MTRX1133 (KRAS G12D) or sotorasib (KRAS G12C) had selective activity in cell lines harboring the corresponding target. Lastly, combination effects were observed from vertical inhibition of the PI3K/AKT/mTOR pathway with a PI3K inhibitor in combination with either the mTORC1/2 inhibitor sapanisertib or an AKT inhibitor, ipatasertib or afuresertib.
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Affiliation(s)
- Thomas S Dexheimer
- Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD, 21702, USA.
| | - Zahra Davoudi
- Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD, 21702, USA
| | - Nathan P Coussens
- Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD, 21702, USA
| | - Thomas Silvers
- Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD, 21702, USA
| | - Joel Morris
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Naoko Takebe
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Rabih Said
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jeffrey A Moscow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - James H Doroshow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Beverly A Teicher
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
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18
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Woolley CE, Domingo E, Fernandez-Tajes J, Pennel KA, Roxburgh P, Edwards J, Richman SD, Maughan TS, Kerr DJ, Soriano I, Tomlinson IP. Coevolution of Atypical BRAF and KRAS Mutations in Colorectal Tumorigenesis. Mol Cancer Res 2025; 23:300-312. [PMID: 39751654 PMCID: PMC7617415 DOI: 10.1158/1541-7786.mcr-24-0464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 11/13/2024] [Accepted: 12/30/2024] [Indexed: 01/04/2025]
Abstract
BRAF mutations in colorectal cancer comprise three functional classes: class 1 (V600E) with strong constitutive activation, class 2 with pathogenic kinase activity lower than that of class 1, and class 3 which paradoxically lacks kinase activity. Non-class 1 mutations associate with better prognosis, microsatellite stability, distal tumor location, and better anti-EGFR response. An analysis of 13 colorectal cancer cohorts (n = 6,605 tumors) compared class 1 (n = 709, 10.7% of colorectal cancers), class 2 (n = 31, 0.47%), and class 3 (n = 81, 1.22%) mutations. Class 2-mutant and class 3-mutant colorectal cancers frequently co-occurred with additional Ras pathway mutations (29.0% and 45.7%, respectively, vs. 2.40% in class 1; P < 0.001), often at atypical sites (KRAS noncodon 12/13/61, NRAS, or NF1). Ras pathway activation was highest in class 1 and lowest in class 3, with a greater distal expression of EGFR ligands (amphiregulin/epiregulin) supporting weaker BRAF driver mutations. Unlike class 1 mutants, class 3 tumors resembled chromosomally unstable colorectal cancers in mutation burdens, signatures, driver mutations, and transcriptional subtypes, whereas class 2 mutants displayed intermediate characteristics. Atypical BRAF mutations were associated with longer overall survival than class 1 mutations (HR = 0.25; P = 0.011) but lost this advantage in cancers with additional Ras mutations (HR = 0.94; P = 0.86). This study supports the suggestion that class 3 BRAF mutations amplify existing Ras signaling in a two-mutation model and that the enhancement of weak/atypical Ras mutations may suffice for tumorigenesis, with potentially clinically important heterogeneity in the class 2/3 subgroup. Implications: The heterogeneous nature of BRAF-mutant colorectal cancers, particularly among class 2/3 mutations which frequently harbor additional Ras mutations, highlights the necessity of comprehensive molecular profiling.
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Affiliation(s)
- Connor E. Woolley
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Enric Domingo
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | | | - Kathryn A.F. Pennel
- School of Cancer Science, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Patricia Roxburgh
- School of Cancer Science, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Joanne Edwards
- School of Cancer Science, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Susan D. Richman
- Division of Pathology and Data Analytics, University of Leeds, Leeds, United Kingdom
| | - Tim S. Maughan
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - David J. Kerr
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Ignacio Soriano
- Department of Oncology, University of Oxford, Oxford, United Kingdom
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19
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Cao KY, Zhang D, Bai LB, Yan TM, Chen Y, Jiang YY, Jiang ZH. Targeting NUCKS1 with a fragment of tRNA Asn(GUU) of Chinese yew for the treatment of colorectal cancer. Noncoding RNA Res 2025; 11:38-47. [PMID: 39736854 PMCID: PMC11683283 DOI: 10.1016/j.ncrna.2024.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 10/22/2024] [Accepted: 11/11/2024] [Indexed: 01/01/2025] Open
Abstract
Despite the discovery of numerous oncogenes in colorectal cancer (CRC), the development of associated drugs is limited, posing a significant challenge for CRC treatment. Identification of novel druggable targets is therefore crucial for the therapeutic development of CRC. Here, we report the first investigation on therapeutics targeting the potent oncogene NUCKS1 to suppress cancer progression. NUCKS1-orientated bioinformatics screening of NUCKS1 inhibitors from our library of tRNA fragments originated from medicinal plants identified tRF-T36, a 5' tRNA fragment of tRNAAsn(GUU) of Chinese yew (Taxus chinensis), exhibiting stronger inhibitory effects than taxol against CRC progression. Mechanistically, tRF-T36 binds directly to the 3' UTR of NUCKS1 mRNA to downregulate its expressions via RNAi pathway. High-throughput RNA sequencing indicated that the downregulated NUCKS1 induced by tRF-T36 further inhibits PI3K/Akt pathway, as verified by the significantly efficacy decrease of tRF-T36 mimic in co-treatment with 740Y-P, an agonist of PI3K/Akt pathway. Collectively, our findings emphasize the importance of NUCKS1 as a promising druggable target for CRC. Furthermore, the present study provides the first siRNA sequence, tRF-T36 mimic, as small RNA drug candidate, thereby shedding light on CRC therapeutics.
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Affiliation(s)
- Kai-Yue Cao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau SAR, China
| | - Da Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau SAR, China
| | - Long-Bo Bai
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau SAR, China
| | - Tong-Meng Yan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau SAR, China
| | - Yan Chen
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China
| | - Yu-Yang Jiang
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, Guangdong, China
| | - Zhi-Hong Jiang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau SAR, China
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20
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Li J, Wang C, Yang C, Bao H, Li N, Huang X, Gong W, Hong X, Yin JC, Pang J, Gan M, Yuan D. Identification of clinicopathological-specific driver gene and genetic subtyping of colorectal cancer. Cancer Sci 2025; 116:1068-1081. [PMID: 39797621 PMCID: PMC11967266 DOI: 10.1111/cas.16432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 11/18/2024] [Accepted: 11/30/2024] [Indexed: 01/13/2025] Open
Abstract
This study analyzed targeted sequencing data from 6530 tissue samples from patients with metastatic Chinese colorectal cancer (CRC) to identify low mutation frequency and subgroup-specific driver genes, using three algorithms for overall CRC as well as across different clinicopathological subgroups. We analyzed 425 cancer-related genes, identifying 101 potential driver genes, including 36 novel to CRC. Notably, some genes demonstrated subgroup specificity; for instance, ERBB4 was found as a male-specific driver gene and mutations of ERBB4 only influenced the prognosis of male patients with CRC. This sex disparity of ERBB4 was validated in an independent large-scale Memorial Sloan Kettering Cancer Center CRC cohort with 2444 samples. Furthermore, using network-based stratification based on protein-protein interaction, we classified the microsatellite stable (MSS) and unstable (MSI) CRCs into six and three major subtypes, respectively, each showing unique phenotypes and prognoses. In MSS CRC, cluster 5 (APCAMER1-KRAS) and cluster 2 (RNF43-BRAF-PIK3CA) were predominant, and cluster 5 showed a superior overall survival compared with cluster 2. This extensive heterogeneity in driver gene mutations underscores the complexity of CRC and suggests significant implications for treatment and prognostic assessments.
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Affiliation(s)
- Jianjiong Li
- Department of Colorectal and Anal SurgeryNingbo No. 2 HospitalNingboChina
| | - Chunnian Wang
- Department of PathologyNingbo Diagnostic Pathology CenterNingboChina
| | - Changshun Yang
- Department of Surgical OncologyShengli Clinical Medical College of Fujian Medical UniversityFuzhouChina
| | - Hua Bao
- Nanjing Geneseeq Technology Inc.NanjingChina
| | - Ningyou Li
- Nanjing Geneseeq Technology Inc.NanjingChina
| | - Xianqiang Huang
- Department of SurgeryQuanzhou Guangqian HospitalQuanzhouChina
| | - Wei Gong
- Department of Radiation OncologyQuanzhou Guangqian HospitalQuanzhouChina
| | - Xinyue Hong
- Nanjing Geneseeq Technology Inc.NanjingChina
| | | | | | - Meifu Gan
- Department of PathologyTaizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical UniversityWenzhouChina
| | - Danping Yuan
- Department of colorectal surgeryThe First Affiliated Hospital of Ningbo UniversityNingboChina
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21
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El Hage M, Su Z, Linnebacher M. Addressing Challenges in Targeted Therapy for Metastatic Colorectal Cancer. Cancers (Basel) 2025; 17:1098. [PMID: 40227578 PMCID: PMC11988006 DOI: 10.3390/cancers17071098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 03/21/2025] [Accepted: 03/22/2025] [Indexed: 04/15/2025] Open
Abstract
This review article aims to address the challenges associated with targeted therapy for the treatment of metastatic colorectal cancer (mCRC). We will first provide an overview of approved targeted therapies for treating mCRC, which include antiangiogenic therapy, as well as inhibitors of EGFR, BRAFV600E, HER2 inhibitors, and immune checkpoints. Second, we discuss the different mechanisms of primary resistance, including tumor heterogeneity, both as inter-patient and intra-patient heterogeneity, and mechanisms of secondary resistance which include: driver oncogene alterations, downstream or parallel bypass signaling, presence of co-dominant driver oncogenes, tumor lineage plasticity, and epithelial to mesenchymal transition. Resistance mechanisms towards the different drug classes targeting mCRC are discussed in detail. Strategies to overcome resistance primarily involve combination of therapies, although this approach is typically linked to increased drug toxicity, manifesting as on and off-target effects. Moreover, the cost and accessibility of targeted therapies pose significant challenges for diverse populations. Addressing these challenges necessitates further research efforts aimed at optimizing the use of targeted therapy in mCRC. Integration of genomic biomarkers, such as sequencing and liquid biopsy, into routine clinical practice holds promise in enhancing treatment outcomes. In conclusion, this comprehensive review underscores the complex challenges encountered in targeted therapy for mCRC.
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Affiliation(s)
| | | | - Michael Linnebacher
- Molecular Oncology and Immunotherapy, Clinic of General Surgery, Rostock University Medical Center, 18057 Rostock, Germany; (M.E.H.); (Z.S.)
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22
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Omer DM, Shah F, Luthra A, Chen CT, Lee CI, Williams H, Walch H, Verheij FS, Rosen R, Alvarez J, Firat C, Karagkounis G, Weiser MR, Widmar M, Wei IH, Pappou EP, Nash GM, Smith JJ, Chatila WK, Romesser PB, Shia J, Paty PB, Garcia-Aguilar J, Sanchez-Vega F. Clinical and Genomic Characterization of Secondary Rectal Cancer After Radiotherapy for Prostate Cancer. JAMA Netw Open 2025; 8:e251039. [PMID: 40100215 PMCID: PMC11920846 DOI: 10.1001/jamanetworkopen.2025.1039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/15/2025] [Indexed: 03/20/2025] Open
Abstract
Importance Patients treated with radiotherapy (RT) for prostate cancer (PC) have increased risk of secondary rectal cancer (SRC) and more limited treatment options. Objective To assess the tumor molecular profile, clinical characteristics, and oncologic outcomes of SRC after PC and compare them with those of primary rectal cancer (PRC). Design, Setting, and Participants This case-control study included patients with SRC diagnosed 5 or more years after RT for PC and patients with PRC who were treated at Memorial Sloan Kettering Cancer Center in New York between February 1, 1994, and September 31, 2022. Main Outcomes and Measures Clinical information and DNA sequencing data were analyzed. Oncologic outcomes were compared between patients with SRC and clinically matched patients with PRC using log-rank tests and Cox proportional hazards regression models. Numerical and categorical variables were compared using the Wilcoxon rank sum test and Fisher exact test, respectively. Results The analysis included 604 male patients with PRC (71.6%; median age, 55 [IQR, 46-66] years) and 64 male patients with SRC (median age, 78 [IQR, 72-82] years). Patients with SRC had more distal rectum (37 of 63 [58.7%] vs 131 of 581 [22.5%]; P < .001) and anterior rectal wall (20 of 57 [35.1%] vs 67 of 496 [13.5%]; P < .001) tumors, were less likely to receive neoadjuvant treatment (33 of 64 [51.6%] vs 570 of 604 [94.4%]), and had shorter 5-year overall survival (45.7% vs 64.9%; P = .01) and disease-free survival (40.3% vs 71.2%; P = .006) compared with clinically matched patients with PRC. Targeted DNA sequencing data from 31 SRC tumors identified lower mutational burden (median, 4.4 [IQR, 3.2-6.7] per megabase [Mb] vs 5.8 [IQR, 4.4-7.0] per Mb; P = .047), lower frequency of APC alterations (15 [48.4%] vs 432 [79.9%]; P < .001), and higher rates of SMAD4 inactivation (8 [25.8%] vs 54 [10.0%]; P = .01) compared with 541 PRC tumors. Whole-exome sequencing data from 17 SRC tumors identified a higher rate of frameshift deletions compared with 28 PRC tumors (median, 5.0 [IQR, 4.0-9.0] vs 2.5 [IQR, 1.0-4.2] variants; P < .001). Conclusions and Relevance In this case-control study, patients with SRC after RT for PC had worse survival and different molecular profiles than patients with PRC. These findings may help improve the clinical management of SRC.
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Affiliation(s)
- Dana M. Omer
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Farheen Shah
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Anisha Luthra
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Chin-Tung Chen
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Christina I. Lee
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Hannah Williams
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Henry Walch
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Floris S. Verheij
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Roni Rosen
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Janet Alvarez
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Canan Firat
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Georgios Karagkounis
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Martin R. Weiser
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Maria Widmar
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Iris H. Wei
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Emmanouil P. Pappou
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Garrett M. Nash
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - J. Joshua Smith
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Walid K. Chatila
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Paul B. Romesser
- Department of Radiation Oncology, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Philip B. Paty
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Julio Garcia-Aguilar
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Francisco Sanchez-Vega
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
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23
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Trelford CB, Shepherd TG. Insights into targeting LKB1 in tumorigenesis. Genes Dis 2025; 12:101402. [PMID: 39735555 PMCID: PMC11681833 DOI: 10.1016/j.gendis.2024.101402] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 06/03/2024] [Accepted: 06/22/2024] [Indexed: 12/31/2024] Open
Abstract
Genetic alterations to serine-threonine kinase 11 (STK11) have been implicated in Peutz-Jeghers syndrome and tumorigenesis. Further exploration of the context-specific roles of liver kinase B1 (LKB1; encoded by STK11) observed that it regulates AMP-activated protein kinase (AMPK) and AMPK-related kinases. Given that both migration and proliferation are enhanced with the loss of LKB1 activity combined with the prevalence of STK11 genetic alterations in cancer biopsies, LKB1 was marked as a tumor suppressor. However, the role of LKB1 in tumorigenesis is paradoxical as LKB1 activates autophagy and reactive oxygen species scavenging while dampening anoikis, which contribute to cancer cell survival. Due to the pro-tumorigenic properties of LKB1, targeting LKB1 pathways is now relevant for cancer treatment. With the recent successes of targeting LKB1 signaling in research and clinical settings, and enhanced cytotoxicity of chemical compounds in LKB1-deficient tumors, there is now a need for LKB1 inhibitors. However, validating LKB1 inhibitors is challenging as LKB1 adaptor proteins, nucleocytoplasmic shuttling, and splice variants all manipulate LKB1 activity. Furthermore, STE-20-related kinase adaptor protein (STRAD) and mouse protein 25 dictate LKB1 cellular localization and kinase activity. For these reasons, prior to assessing the efficacy and potency of pharmacological candidates, the functional status of LKB1 needs to be defined. Therefore, to improve the understanding of LKB1 in physiology and oncology, this review highlights the role of LKB1 in tumorigenesis and addresses the therapeutic relevancy of LKB1 inhibitors.
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Affiliation(s)
- Charles B. Trelford
- The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON N6A 4L6, Canada
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Trevor G. Shepherd
- The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON N6A 4L6, Canada
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Obstetrics and Gynaecology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
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24
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Venetis K, Frascarelli C, Bielo LB, Cursano G, Adorisio R, Ivanova M, Mane E, Peruzzo V, Concardi A, Negrelli M, D'Ercole M, Porta FM, Zhan Y, Marra A, Trapani D, Criscitiello C, Curigliano G, Guerini-Rocco E, Fusco N. Mismatch repair (MMR) and microsatellite instability (MSI) phenotypes across solid tumors: A comprehensive cBioPortal study on prevalence and prognostic impact. Eur J Cancer 2025; 217:115233. [PMID: 39827722 DOI: 10.1016/j.ejca.2025.115233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 01/08/2025] [Indexed: 01/22/2025]
Abstract
Mismatch repair deficiency (MMR-d) and microsatellite instability (MSI) are prognostic and predictive biomarkers in oncology. Current testing for MMR/MSI relies on immunohistochemistry (IHC) for MMR proteins and molecular assays for MSI detection. This combined diagnostic strategy, however, lacks tumor specificity and does not account for gene variants. This study provides an in-depth analysis of MMR mutations frequency, spectrum, and distribution in solid tumors. Data from 23,893 patients across 11 tumor types, using 66 publicly available studies, were analyzed. MMR-mutated (MMR-m) status was defined by alterations in MLH1, PMS2, MSH2, and/or MSH6; MSI was assessed by MSIsensor. Cases with indeterminate labelling were excluded. Survival was analyzed using the Kaplan-Meier method. Among 19,353 tumors, 949 MMR variants were identified, comprising 432 pathogenic and 517 variants of unknown significance (VUS), as defined by OncoKB. MSH6 mutations were the most frequent (n = 279, 29.4 %), followed by MSH2 (n = 198, 20.9 %), MLH1 (n = 187, 19.7 %), and PMS2 (n = 161, 16.9 %). MMR-m cases were more frequent in endometrial (EC, 20.5 %), colorectal (CRC, 8.2 %), bladder (BLCA, 8.7 %), and gastroesophageal cancers (GEC, 5.4 %). Pathogenic mutations were more common than non-pathogenic in EC, CRC, and GEC (p < 0.001, p = 0.01, p = 0.32, respectively). MMR-m status was not associated with MSI in 247 (48.9 %) cases, including 67 (13.2 %) with pathogenic mutations. The highest concordance between MMR-m and MSI was observed in CRC (65.7 %), EC (91.2 %), and GEC (69.6 %), while the lowest in pancreatic (0.2 %) and lung cancers (0.1 %). MMR-m GECs showed improved overall survival compared to MMR-wt (p = 0.009), a relationship not observed in other tumor types. This study demonstrates that the MMR spectrum is extremely hetoerogeneous in solid tumors, highliting the need for comprehensive and tumor-specific testing strategies.
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Affiliation(s)
| | - Chiara Frascarelli
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Luca Boscolo Bielo
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Giulia Cursano
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Riccardo Adorisio
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | - Mariia Ivanova
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | - Eltjona Mane
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | - Virginia Peruzzo
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | - Alberto Concardi
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | | | - Marianna D'Ercole
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | | | - Yinxiu Zhan
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - Antonio Marra
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Dario Trapani
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Carmen Criscitiello
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Giuseppe Curigliano
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Elena Guerini-Rocco
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Nicola Fusco
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
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Mahmoud A, Choi PH, Sukhwa C, Pintar J, Walch H, Zhao N, Bermeo J, Chung S, Raghavan M, Bapat S, Jiang Q, Karagkounis G, Meredith J, Giarrizzo M, Firat C, Cercek A, Foote MB, Schultz N, Chatila WK, Nash GM, Shia J, Sanchez-Vega F, Larson S, Dar AC, Rosen N, Ganesh K. Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.17.638725. [PMID: 40027618 PMCID: PMC11870485 DOI: 10.1101/2025.02.17.638725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Peritoneal carcinomatosis is a common yet deadly manifestation of gastrointestinal cancers, with few effective treatments. To identify targetable determinants of peritoneal metastasis, we focused on appendiceal adenocarcinoma (AC), a gastrointestinal cancer that metastasizes almost exclusively to the peritoneum. Current treatments are extrapolated from colorectal cancer (CRC), yet AC has distinct genomic alterations, mucinous morphology and peritoneum restricted metastatic pattern. Further, no stable preclinical models of AC exist, limiting drug discovery and representing an unmet clinical need. We establish a first-in-class stable biobank of 16 long-term cultured AC patient-derived organoids (PDOs), including 3 matched, simultaneously resected primary AC-peritoneal carcinomatosis (AC-PC) pairs. By enriching for cancer cells, AC PDOs enable accurate genomic characterization relative to paucicellular AC tissue. We establish an organoid orthotopic intraperitoneal xenograft model that recapitulates diffuse peritoneal carcinomatosis and show that PC-organoids retain increased metastatic capacity, decreased growth factor dependency and sensitivity to standard of care chemotherapy relative to matched primary AC organoids. Single cell profiling of AC-PC pairs reveals dedifferentiation from mucinous differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. Through hypothesis-driven drug testing, we identify KRASMULTI-ON inhibitor RMC-7977 and Wnt-targeting tyrosine kinase inhibitor WNTinib as novel, clinically actionable strategies to target AC-PC more effectively.
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Affiliation(s)
- Ahmed Mahmoud
- Pharmacology Program, Weill Cornell Graduate School, New York, NY, USA
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Philip H. Choi
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Christine Sukhwa
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jura Pintar
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Henry Walch
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nan Zhao
- Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jonathan Bermeo
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sebastian Chung
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Manisha Raghavan
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Samhita Bapat
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Qingwen Jiang
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Georgios Karagkounis
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Julia Meredith
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Giarrizzo
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Canan Firat
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA
| | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael B. Foote
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Walid K. Chatila
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Garrett M. Nash
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA
| | - Francisco Sanchez-Vega
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Steven Larson
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Arvin C. Dar
- Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Neal Rosen
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Karuna Ganesh
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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26
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Wang D, Wang L, Zhang W, Xu K, Chen L, Guo Z, Wu K, Huang D, Zhao Y, Yao M, Zheng L, Ye C, Ran J, Zhou W, Liu X, Xu J. Extracellular vesicle-mediated gene therapy targets BRAF V600E-mutant colorectal cancer by inhibiting the MEK1/2-ERK1/2 pathway. J Nanobiotechnology 2025; 23:129. [PMID: 39979881 PMCID: PMC11843959 DOI: 10.1186/s12951-025-03205-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/05/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Patients with colorectal cancer (CRC) harboring BRAF mutation have a poor prognosis. The median survival time for patients with advanced BRAFV600E-mutant CRC is only approximately one year. Owing to the insensitivity to standard chemotherapy, there are still no effective and highly specific treatment strategies available in clinical practice for CRC patients with BRAF mutation. Therefore, targeting the BRAFV600E mutation site, researching and exploring novel targeted therapies are essential to improve the survival rate of patients with this CRC subtype. AIM This study aims to develop a precise therapeutic system for BRAFV600E CRC, based on the carrier properties of extracellular vesicles (EVs) and gene therapy targeting BRAFV600E. METHOD We first obtained engineered cells capable of stably producing EVs loaded with BRAFV600E nucleic acid drugs (siBRAFV600E). Next, BRAFV600E-mutant and wild-type CRC cell lines, as well as corresponding subcutaneous and metastasis models, were used to evaluate the therapeutic efficacy of EVs-siBRAFV600E and explored the mechanism. Notably, patient-derived xenograft (PDX) models, which share the same molecular characteristics, pathological features, and heterogeneity as patients do, were utilized to further explore the therapeutic efficacy and mechanisms. RESULT EVs-siBRAFV600E specifically inhibited BRAFV600E CRC but didn't affect BRAF wild-type CRC in vitro and vivo. EVs-siBRAFV600E exerts its therapeutic effect by regulating the MEK1/2-ERK1/2 pathway, and it has demonstrated excellent therapeutic efficacy in PDX models. CONCLUSION The therapeutic EVs we constructed are effective and specific for the BRAFV600E-mutant CRC. This study provides a novel strategy for the treatment of CRC patients with BRAFV600E mutation.
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Affiliation(s)
- Di Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Liwei Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Wei Zhang
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, PR China
| | - Kaicheng Xu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Liang Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Ziye Guo
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Kaile Wu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Donghua Huang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Yubin Zhao
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Minjun Yao
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Liming Zheng
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Chenyi Ye
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Jisheng Ran
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Wei Zhou
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, PR China.
| | - Xin Liu
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, PR China.
| | - Jianbin Xu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China.
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China.
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China.
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China.
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27
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Zhao C, Lou X, Jia W, Wan Z, Lu X, Qiu Y, Xu Q, Jian K, Zhang H, Liang F. Sample size required for prognostic genes analysis in colorectal cancer. Discov Oncol 2025; 16:209. [PMID: 39971824 PMCID: PMC11839551 DOI: 10.1007/s12672-025-01962-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 02/10/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Different colorectal cancer (CRC) studies rarely report overlapping prognostic genes. This study aimed to investigate the effects of sample size on prognostic genes analysis in CRC. METHODS We included 418 CRC cases detected by whole-exome sequencing (WES) in the TCGA PanCancer cohort and 931 CRC cases detected by targeted sequencing in the MSK cohort. Prognostic genes analysis was repeated 200 times at each sample size level using a random resampling method. RESULTS For WES data, the number of prognostic genes increased in a power-law with increasing sample size in CRC cases with stage III and IV. This pattern also applied to CRC patients with stage II after the removal of patients with MSI-H or POLE mutations. However, for targeted sequencing data, the number of prognostic genes increased linearly with increasing sample size in CRC cases with stage III and IV. About 550 cases were required for stage IV CRC to reach the plateau of prognostic genes. In both cohorts, the proportion of true prognostic genes relative to sample size was consistent with a binomial distribution, indicating a significant effect of sample size on the reliability of prognostic genes. At the same sample size level, the number of prognostic genes from the WES data was higher than that from the targeted sequencing data, while the reliability of prognostic genes from the WES data was lower. CONCLUSION This study shows the relationship between the number of prognostic genes and sample size in CRC and how mutation data affects this relationship. This will contribute to the trial design for prognostic genetic analysis in CRC.
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Affiliation(s)
- Chuanhua Zhao
- Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China
| | - Xiao Lou
- Department of Hematology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China
| | - Weilu Jia
- Medical School, Southeast University, Nanjing, 210009, China
| | - Zhiyi Wan
- Genecast Biotechnology Co., Ltd, Wuxi, 214104, China
| | - Xin Lu
- Department of General Surgery, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yuxuan Qiu
- Department of General Surgery, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Qianru Xu
- Department of General Surgery, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Kaiyu Jian
- Department of General Surgery, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Hongyan Zhang
- Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China.
| | - Feng Liang
- Department of General Surgery, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
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28
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Hebert JD, Tang YJ, Szamecz M, Andrejka L, Lopez SS, Petrov DA, Boross G, Winslow MM. Combinatorial In Vivo Genome Editing Identifies Widespread Epistasis and an Accessible Fitness Landscape During Lung Tumorigenesis. Mol Biol Evol 2025; 42:msaf023. [PMID: 39907430 PMCID: PMC11824425 DOI: 10.1093/molbev/msaf023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 11/15/2024] [Accepted: 01/15/2025] [Indexed: 02/06/2025] Open
Abstract
Lung adenocarcinoma, the most common subtype of lung cancer, is genomically complex, with tumors containing tens to hundreds of non-synonymous mutations. However, little is understood about how genes interact with each other to enable the evolution of cancer in vivo, largely due to a lack of methods for investigating genetic interactions in a high-throughput and quantitative manner. Here, we employed a novel platform to generate tumors with inactivation of pairs of ten diverse tumor suppressor genes within an autochthonous mouse model of oncogenic KRAS-driven lung cancer. By quantifying the fitness of tumors with every single and double mutant genotype, we show that most tumor suppressor genetic interactions exhibited negative epistasis, with diminishing returns on tumor fitness. In contrast, Apc inactivation showed positive epistasis with the inactivation of several other genes, including synergistic effects on tumor fitness in combination with Lkb1 or Nf1 inactivation. Sign epistasis was extremely rare, suggesting a surprisingly accessible fitness landscape during lung tumorigenesis. These findings expand our understanding of the interactions that drive tumorigenesis in vivo.
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Affiliation(s)
- Jess D Hebert
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Yuning J Tang
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Márton Szamecz
- Faculty of Informatics, Eötvös Loránd University, Budapest, Hungary
- National Laboratory for Health Security, Centre for Eco-Epidemiology, Budapest, Hungary
- Institute of Evolution, HUN-REN Centre for Ecological Research, Budapest, Hungary
| | - Laura Andrejka
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Steven S Lopez
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Dmitri A Petrov
- Department of Biology, Stanford University, Stanford, CA, USA
- Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Gábor Boross
- National Laboratory for Health Security, Centre for Eco-Epidemiology, Budapest, Hungary
- Institute of Evolution, HUN-REN Centre for Ecological Research, Budapest, Hungary
| | - Monte M Winslow
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
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29
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Andrysik Z, Espinosa JM. Harnessing p53 for targeted cancer therapy: new advances and future directions. Transcription 2025; 16:3-46. [PMID: 40031988 PMCID: PMC11970777 DOI: 10.1080/21541264.2025.2452711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 03/05/2025] Open
Abstract
The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.
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Affiliation(s)
- Zdenek Andrysik
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Joaquin M. Espinosa
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Adorisio R, Ciardiello D, Rappa A, Gervaso L, Pelizzari G, Marinucci L, Fusco N, Zampino MG, Fazio N, Venetis K, Guerini-Rocco E. Investigating the Pathogenicity of Uncommon KRAS Mutations and Their Association with Clinicopathologic Characteristics in Patients with Colorectal Cancer. J Mol Diagn 2025; 27:130-138. [PMID: 39694458 DOI: 10.1016/j.jmoldx.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/11/2024] [Accepted: 11/12/2024] [Indexed: 12/20/2024] Open
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) somatic mutations occur in 30% to 40% of patients with colorectal cancer (CRC). These were thought to equally affect prognosis and resistance to anti-epidermal growth factor receptor agents; however, recent data show the activity of KRAS-G12C and pan-RAS inhibitors. The effects of uncommon KRAS (uKRAS) variants are largely unexplored. The distribution and pathogenicity of uKRAS mutations and their relationship with patients' clinicopathologic features were assessed. A total of 2427 CRCs were profiled for KRAS using next-generation sequencing (NGS). The study and control groups included patients with uKRAS (<1% frequency in CRC data sets on cBioPortal) and canonical KRAS mutations, respectively. In silico protein structure modifications and prediction analyses were performed by using PyMOL, trRosetta, and PolyPhen-2. uKRAS mutations affected 35 cases (1.5%), with G13C (28.6%), G12R (20%), and V14I (8.6%) being most common. Missense mutations (D33E, G12W, G12F, Q22H, Q61L, and L19F) occurred in nine cases (25.7%). Duplications (G10dup and L52_G60dup) affected two cases. Pathogenicity analyses showed that G12W, Q22R, L56V, and A130I mutations are probably damaging, with scores between 0.928 and 1.000. No differences were seen in clinicopathologic features. uKRAS mutants had lower event-free survival but no difference in overall survival compared with controls. Although these data are hypothesis generating and need further confirmation, they highlight the importance of NGS-based profiling to identify CRC patients with uKRAS mutations as candidates for personalized therapy.
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Affiliation(s)
- Riccardo Adorisio
- Division of Pathology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Davide Ciardiello
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy
| | - Alessandra Rappa
- Division of Pathology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Lorenzo Gervaso
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy
| | - Gloria Pelizzari
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Division of Early Drug Development, European Institute of Oncology, IRCCS, Milan, Italy
| | - Laura Marinucci
- Division of Haematopathology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Nicola Fusco
- Division of Pathology, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Maria Giulia Zampino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy
| | | | - Elena Guerini-Rocco
- Division of Pathology, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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31
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Coelho D, Estêvão D, Oliveira MJ, Sarmento B. Radioresistance in rectal cancer: can nanoparticles turn the tide? Mol Cancer 2025; 24:35. [PMID: 39885557 PMCID: PMC11784129 DOI: 10.1186/s12943-025-02232-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Accepted: 01/14/2025] [Indexed: 02/01/2025] Open
Abstract
Rectal cancer accounts for over 35% of the worldwide colorectal cancer burden representing a distinctive subset of cancers from those arising in the colon. Colorectal cancers exhibit a continuum of traits that differ with their location in the large intestine. Due to anatomical and molecular differences, rectal cancer is treated differently from colon cancer, with neoadjuvant chemoradiotherapy playing a pivotal role in the control of the locally advanced disease. However, radioresistance remains a major obstacle often correlated with poor prognosis. Multifunctional nanomedicines offer a promising approach to improve radiotherapy response rates, as well as to increase the intratumoral concentration of chemotherapeutic agents, such as 5-Fluorouracil. Here, we revise the main molecular differences between rectal and colon tumors, exploring the complex orchestration beyond rectal cancer radioresistance and the most promising nanomedicines reported in the literature to improve neoadjuvant therapy response rates.
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Affiliation(s)
- Diogo Coelho
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- IUCS - Instituto Universitário de Ciências da Saúde, CESPU, Rua Central de Gandra 1317, Gandra, 4585-116, Portugal
| | - Diogo Estêvão
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Cancer Research Institute, Ghent University, Ghent, Belgium
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, Porto, 4200-319, Portugal
| | - Maria José Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, Porto, 4200-319, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal.
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal.
- IUCS - Instituto Universitário de Ciências da Saúde, CESPU, Rua Central de Gandra 1317, Gandra, 4585-116, Portugal.
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Taniguchi H, Uehara K, Ishikawa T, Okochi O, Akazawa N, Okuda H, Hasegawa H, Shiozawa M, Kataoka M, Satake H, Shimura T, Kondoh C, Kuramochi H, Matsumoto T, Takegawa N, Yamaguchi T, Nagase M, Nakamura M, Takano N, Fujita H, Watanabe T, Nishina T, Sakamoto Y, Moriwaki T, Ohori H, Nakanishi M, Kito Y, Utsunomiya S, Ishikawa T, Manaka D, Matsuoka H, Suto T, Arai T, Shinzaki S, Funakoshi T, Nakayama G, Negoro Y, Tsuji Y, Makiyama A, Takuma K, Arimoto A, Shinozaki K, Mishima A, Masuishi T. BRAF V600E and Non-V600E Mutations in RAS Wild-Type Metastatic Colorectal Cancer: Prognostic and Therapeutic Insights from a Nationwide, Multicenter, Observational Study (J-BROS). Cancers (Basel) 2025; 17:399. [PMID: 39941768 PMCID: PMC11815755 DOI: 10.3390/cancers17030399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND/OBJECTIVES BRAF mutations occur in 5-10% of metastatic colorectal cancer (mCRC) cases, but their implications for prognosis and optimal treatment remain unclear. METHODS This multicenter, prospective observational study analyzed 377 RAS wild-type cases from 511 patients across 32 centers, using PCR-based methods. RESULTS BRAF mutations were identified in 21% (79/377) of cases, predominantly V600E (89.9%) with a minority of non-V600E (10.1%). Microsatellite instability (MSI) testing revealed MSI-high in 11.3%, exclusively among V600E cases. V600E mutations were linked to right-sided tumors, poor differentiation, and elevated CA19-9 levels. Median survival was significantly lower in V600E cases compared to BRAF wild-type (12.4 vs. 37.5 months, HR 3.25, p < 0.001) and marginally lower non-V600E cases (12.4 vs. 34.7 months, HR 0.61, p = 0.057). Chemotherapy regimens (doublet vs. triplet) and targeted treatments (bevacizumab vs. anti-EGFR) showed no significant survival differences in V600E patients. Similarly, RAS/BRAF wild-type patients had comparable survival with bevacizumab versus anti-EGFR, even for left-sided tumors. CONCLUSIONS These findings highlight distinct clinical and prognostic profiles for BRAF V600E and non-V600E mutations, while treatment choice appears to have limited impact on survival in these subgroups or RAS/BRAF wild-type cases.
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Affiliation(s)
- Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Kay Uehara
- Department of Gastroenterological Surgery, Nagoya University Hospital, Nagoya 466-8560, Japan
- Department of Gastroenterological Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Toshiaki Ishikawa
- Department of Specialized Surgeries, Institute of Science Tokyo, Tokyo 113-8519, Japan
- Department of Medical Oncology, Juntendo University, Tokyo 113-8431, Japan
| | - Osamu Okochi
- Department of Surgery, Tosei General Hospital, Seto 489-8642, Japan
| | - Naoya Akazawa
- Department of Gastroenterological Surgery, Sendai City Medical Center Sendai Open Hospital, Sendai 983-0824, Japan
| | - Hiroyuki Okuda
- Department of Clinical Oncology, Keiyukai Sapporo Hospital, Sapporo 003-0026, Japan
| | - Hiroko Hasegawa
- Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka 540-0006, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama 241-0815, Japan
| | - Masato Kataoka
- Department of Surgery, NHO Nagoya Medical Center, Nagoya 460-0001, Japan
| | - Hironaga Satake
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan
- Department of Medical Oncology, Kochi Medical School, Nankoku 783-8505, Japan
| | - Takaya Shimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8602, Japan
| | - Chihiro Kondoh
- Department of Medical Oncology, Toranomon Hospital, Tokyo 105-8470, Japan
- Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
| | - Hidekazu Kuramochi
- Department of Chemotherapy, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo 276-8524, Japan
- Department of Medical Oncology, NTT Medical Center Tokyo, Tokyo 141-8625, Japan
| | - Toshihiko Matsumoto
- Department of Internal medicine, Himeji Red Cross Hospital, Himeji 670-8540, Japan
- Department of Medical Oncology, Ichinomiyanishi Hospital, Ichinomiya 494-0001, Japan
| | - Naoki Takegawa
- Department of Gastroenterology, Hyogo Cancer Center, Akashi 673-8558, Japan
| | - Toshifumi Yamaguchi
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki 569-0801, Japan
| | - Michitaka Nagase
- Department of Medical Oncology, Saku Central Hospital Advanced Care Center, Saku 385-0051, Japan
| | - Masato Nakamura
- Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto 390-8510, Japan
| | - Nao Takano
- Department of Surgery, Tokai Central Hospital, Kagamihara 504-8601, Japan
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya 466-8560, Japan
| | - Hideto Fujita
- Department of General and Digestive surgery, Kanazawa Medical University, Uchinadamachi 920-0293, Japan
| | - Takanori Watanabe
- Department of Surgery, Japanese Red Cross Society Himeji Hospital, Himeji 670-8540, Japan
- Department of Surgery, Tokushima Municipal Hospital, Tokushima 770-0812, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama 791-0245, Japan
| | - Yasuhiro Sakamoto
- Department of Medical Oncology, Osaki Citizen Hospital, Osaki 989-6183, Japan
| | - Toshikazu Moriwaki
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8576, Japan
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki 710-8602, Japan
| | - Hisatsugu Ohori
- Department of Medical Oncology, Ishinomaki Red Cross Hospital, Ishinomaki 986-8522, Japan
| | - Masayoshi Nakanishi
- Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
- Department of Surgery, Matsushita Memorial Hospital, Moriguchi 570-8540, Japan
| | - Yosuke Kito
- Department of Medical Oncology, Ishikawa Prefectural Central Hospital, Kanazawa 920-8530, Japan
| | - Setsuo Utsunomiya
- Department of Clinical Oncology, Kainan Hospital, Yatomi 498-8502, Japan
| | - Takeshi Ishikawa
- Outpatient Oncology Unit, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Dai Manaka
- Department of Surgery, Kyoto Katsura Hospital, Kyoto 615-8256, Japan
| | - Hiroshi Matsuoka
- Department of Surgery, Fujita Health University, Toyoake 470-1192, Japan
| | - Takeshi Suto
- Department of Gastroenterological Surgery, Yamagata Prefectural Central Hospital, Yamagata 990-2292, Japan
| | - Toshiyuki Arai
- Department of Surgery, Anjo Kosei Hospital, Anjo 446-8602, Japan
| | - Shinichiro Shinzaki
- Department of Gastroenterology, School of Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Tohru Funakoshi
- Department of Surgery, Asahikawa Kosei General Hospital, Asahikawa 078-8211, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan
| | - Yuji Negoro
- Department of Oncological Medicine, Kochi Health Sciences Center, Kochi 781-8555, Japan
| | - Yasushi Tsuji
- Department of Medical Oncology, Tonan Hospital, Sapporo 060-0004, Japan
| | - Akitaka Makiyama
- Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushyu 806-0034, Japan
- Cancer Center, Gifu University Hospital, Gifu 501-1194, Japan
| | - Kunio Takuma
- Department of Surgery, Tokyo Metropolitan Tama Medical Center, Fuchu 183-8524, Japan
| | - Atsuki Arimoto
- Department of General Surgery, Toyohashi Municipal Hospital, Toyohashi 441-8570, Japan
| | - Katsunori Shinozaki
- Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima 734-8530, Japan
| | - Ayako Mishima
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Toshiki Masuishi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
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Bian JY, Feng YF, He WT, Zhang T. Cohort study on the treatment of BRAF V600E mutant metastatic colorectal cancer with integrated Chinese and western medicine. World J Clin Oncol 2025; 16:93670. [PMID: 39867731 PMCID: PMC11528896 DOI: 10.5306/wjco.v16.i1.93670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 09/04/2024] [Accepted: 10/11/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Patients with BRAF V600E mutant metastatic colorectal cancer (mCRC) have a low incidence rate, poor biological activity, suboptimal response to conventional treatments, and a poor prognosis. In the previous cohort study on mCRC conducted by our team, it was observed that integrated Chinese and Western medicine treatment could significantly prolong the overall survival (OS) of patients with colorectal cancer. Therefore, we further explored the survival benefits in the population with BRAF V600E mutant mCRC. AIM To evaluate the efficacy of integrated Chinese and Western medicine in the treatment of BRAF V600E mutant metastatic colorectal cancer. METHODS A cohort study was conducted on patients with BRAF V600E mutant metastatic colorectal cancer admitted to Xiyuan Hospital of China Academy of Chinese Medical Sciences and Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region from January 2016 to December 2022. The patients were divided into two cohorts. RESULTS A total of 34 cases were included, with 23 in Chinese-Western medicine cohort (cohort A) and 11 in Western medicine cohort (cohort B). The median overall survival was 19.9 months in cohort A and 14.2 months in cohort B, with a statistically significant difference (P = 0.038, hazard ratio = 0.46). The 1-3-year survival rates were 95.65% (22/23), 39.13% (9/23), and 26.09% (6/23) in cohort A, and 63.64% (7/11), 18.18% (2/11), and 9.09% (1/11) in cohort B, respectively. Subgroup analysis showed statistically significant differences in median OS between the two cohorts in the right colon, liver metastasis, chemotherapy, and first-line treatment subgroups (P < 0.05). CONCLUSION Integrated Chinese and Western medicine can prolong the survival and reduce the risk of death in patients with BRAF V600E mutant metastatic colorectal cancer, with more pronounced benefits observed in patients with right colon involvement, liver metastasis, combined chemotherapy, and first-line treatment.
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Affiliation(s)
- Jiang-Yu Bian
- Department of Oncology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Yu-Fang Feng
- Department of Oncology, The Fourth Clinical Medical College of Xinjiang Medical University, Urumqi 830001, China
| | - Wen-Ting He
- Department of Oncology, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi 830001, China
| | - Tong Zhang
- Department of Oncology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
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Villarreal OE, Xu Y, Tran H, Machado A, Prescod D, Anderson A, Minelli R, Peoples M, Martinez AH, Lee HM, Wong CW, Fowlkes N, Kanikarla P, Sorokin A, Alshenaifi J, Coker O, Lin K, Bristow C, Viale A, Shen JP, Parseghian C, Marszalek JR, Corcoran R, Kopetz S. Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.22.634215. [PMID: 39896605 PMCID: PMC11785218 DOI: 10.1101/2025.01.22.634215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
MAPK pathway inhibitors (MAPKi) are increasingly used in the treatment of advanced colorectal cancer, but often produce short-lived responses in patients. Although acquired resistance by de novo mutations in tumors have been found to reduce response in some patients, additional mechanisms underlying the limited response durability of MAPK targeting therapy remain unknown. Here, we denote new contributory tumor biology and provide insight on the impact of tumor plasticity on therapy response. Analysis of MAPKi treated patients revealed activation of stemness programs and increased ASCL2 expression, which are associated with poor outcomes. Greater ASCL2 with MAPKi treatment was also seen in patient-derived CRC models, independent of driver mutations. We find ASCL2 denotes a distinct cell population, arising from phenotypic plasticity, with a proliferative, stem-like phenotype, and decreased sensitivity to MAPKi therapy, which were named adaptive plasticity tumor (APT) cells. MAPK pathway suppression induces the APT phenotype in cells, resulting in APT cell enrichment in tumors and limiting therapy response in preclinical and clinical data. APT cell depletion improved MAPKi treatment efficacy and extended MAPKi response durability in mice. These findings uncover a cellular program that mitigates the impact of MAPKi therapies and highlights the importance of addressing tumor plasticity to improve clinical outcomes.
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Ottaviano KE, Subbaram S, Wu L, Stahl K, Mastrangelo AJ, Lee H, DiPersio CM. Integrin α3β1 Is Not Required for Onset of Dysplasia in Genetic Model of Colon Cancer but Promotes Motility of Colon Cancer Cells. Cancers (Basel) 2025; 17:371. [PMID: 39941740 PMCID: PMC11815772 DOI: 10.3390/cancers17030371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/13/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND/OBJECTIVES The progression of colorectal cancer through clinically and histopathologically well-defined stages is driven by specific mutations that activate oncogenes or inactivate tumor-suppressor genes. In addition, pre-cancerous/cancer cells respond to cues from the tissue microenvironment that support tumorigenesis and progression, many of which are transmitted through integrin receptors for the extracellular matrix. Integrin α3β1 has pro-tumorigenic/pro-metastatic roles in many cancers, but it also has suppressive roles in some cancers or at specific stages of progression, indicating that its potential value as a therapeutic target cannot be extrapolated across cancer types or stages. In this study, we investigated roles for α3β1 in colorectal cancer using cellular and genetic models that represent different stages. METHODS We generated mice with colon-specific α3 knockout in a tamoxifen-inducible model of KRAS-mutated colorectal cancer to assess the effects of α3β1 ablation on early dysplasia. We also used siRNA to suppress α3β1 in human colorectal cancer cells, then assessed effects on motility and invasion in vitro. RESULTS Genetic deletion of α3β1 in the colon did not alter dysplasia in mice predisposed to KRAS-mutated colorectal cancer, and it was accompanied by an increase in the colocalization of α6 integrin with laminin-332 (a matrix ligand for both integrins), suggesting functional compensation. However, suppression of α3β1 caused an approximately 40% to 60% reduction in the motility/invasion of human colorectal cancer cells. CONCLUSIONS Our findings that α3β1 is not required for pre-cancerous dysplasia but promotes colorectal cancer cell motility/invasion indicate an important role for pro-migratory functions of this integrin at later stages of progression when cells invade from the primary tumor, suggesting that strategies to target α3β1 in colorectal cancer should be aimed at distinct stages of disease progression.
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Affiliation(s)
- Kathryn E. Ottaviano
- Department of Surgery, Albany Medical College, Albany, NY 12208, USA; (K.E.O.); (S.S.); (L.W.)
| | - Sita Subbaram
- Department of Surgery, Albany Medical College, Albany, NY 12208, USA; (K.E.O.); (S.S.); (L.W.)
- Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USA; (K.S.); (A.J.M.)
- Department of Biology, Union College, Schenectady, NY 12308, USA
| | - Lei Wu
- Department of Surgery, Albany Medical College, Albany, NY 12208, USA; (K.E.O.); (S.S.); (L.W.)
| | - Kiley Stahl
- Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USA; (K.S.); (A.J.M.)
| | - Antoinette J. Mastrangelo
- Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USA; (K.S.); (A.J.M.)
| | - Hwajeong Lee
- Department of Pathology, Albany Medical College, Albany, NY 12208, USA;
| | - C. Michael DiPersio
- Department of Surgery, Albany Medical College, Albany, NY 12208, USA; (K.E.O.); (S.S.); (L.W.)
- Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USA; (K.S.); (A.J.M.)
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Sun Z, Shi M, Xia J, Li X, Chen N, Wang H, Gao Z, Jia J, Yang P, Ji D, Gu J. HDAC and MEK inhibition synergistically suppresses HOXC6 and enhances PD-1 blockade efficacy in BRAF V600E-mutant microsatellite stable colorectal cancer. J Immunother Cancer 2025; 13:e010460. [PMID: 39800382 PMCID: PMC11749543 DOI: 10.1136/jitc-2024-010460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 12/06/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND B-Raf proto-oncogene, serine/threonine kinase (BRAF)V600E-mutant microsatellite stable (MSS) colorectal cancer (CRC) constitutes a distinct CRC subgroup, traditionally perceived as minimally responsive to standard therapies. Recent clinical attempts, such as BRAF inhibitors (BRAFi) monotherapy and combining BRAFi with other inhibitors, have yielded unsatisfactory efficacy. This study aims to identify a novel therapeutic strategy for this challenging subgroup. METHODS We first performed a large-scale drug screening using patient-derived organoid models and cell lines to pinpoint potential therapies. Subsequently, we investigated the synergistic effects of identified effective inhibitors and probed their cooperative mechanisms. Concurrently, we explored the immune characteristics of BRAFV600E MSS CRC using RNA sequencing and multiplex immunohistochemistry. Finally, we established a CT26 BRAFV637E mouse cell line and validated the efficacy of combining these inhibitors and programmed death 1 (PD-1) blockades in immunocompetent mice. RESULTS Drug screening identified histone deacetylase (HDAC) inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor as significantly effective against BRAFV600E MSS CRC. Further research revealed that these two inhibitors have superior synergistic effects by comprehensively inhibiting the activation of the epidermal growth factor receptor, mitogen-activated protein kinase, and phosphoinositide 3-kinase-protein kinase B pathways and suppressing the key target homeobox C6 (HOXC6). HOXC6, overexpressed in BRAFV600E MSS CRC, regulates the MYC gene and contributes to treatment resistance, tumor growth, and metastasis. Moreover, the combination therapy demonstrated the ability to enhance antitumor immunity by synergistically upregulating the expression of immune activation-related genes, activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway, and diminishing the tumor cells' DNA mismatch repair capacity. Notably, BRAFV600E MSS CRC was identified to exhibit a distinct immune microenvironment with increased PD-1+ cell infiltration and potential responsiveness to immunotherapy. Echoing the above findings, in vivo, HDAC and MEK inhibitors significantly improved PD-1 blockade efficacy, accompanied by increased CD8+ T-cell infiltration. CONCLUSIONS Our findings indicate that combining HDAC inhibitor, MEK inhibitor, and PD-1 blockade is a potential strategy for treating BRAFV600E-mutant MSS CRC, warranting further investigation in clinical settings.
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Affiliation(s)
- Zhuang Sun
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Mengyuan Shi
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jinhong Xia
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xin Li
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Nan Chen
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hanyang Wang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhaoya Gao
- Peking University Shougang Hospital, Beijing, China
| | - Jinying Jia
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Peng Yang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Dengbo Ji
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jin Gu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
- Peking University Shougang Hospital, Beijing, China
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Ding H, Yuan M, Yang Y, Xu XS. Longitudinal genomic profiling using liquid biopsies in metastatic nonsquamous NSCLC following first line immunotherapy. NPJ Precis Oncol 2025; 9:5. [PMID: 39779891 PMCID: PMC11711381 DOI: 10.1038/s41698-024-00797-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 12/27/2024] [Indexed: 01/11/2025] Open
Abstract
Tumor genomic profiling is often limited to one or two timepoints due to the invasiveness of tissue biopsies, but longitudinal profiling may provide deeper clinical insights. Using ctDNA data from IMpower150 study, we examined genetic changes in metastatic non-squamous NSCLC post-first-line immunotherapy. Mutations were most frequently detected in TP53, KRAS, SPTA1, FAT3, and LRP1B at baseline and during treatment. Mutation levels rose prior to radiographic progression in most progressing patients, with specific mutations (SPTA1, STK11, KEAP1, SMARCA4, TBX3, CDH2, and MLL3) significantly enriched in those with progression or nondurable response. However, ctDNA's role in detecting hyperprogression and pseudoprogression remains uncertain. STK11, SMARCA4, KRAS, SLT2, and KEAP1 mutations showed the strongest correlation with poorer overall survival, while SMARCA4, STK11, SPTA1, TBX3, and KEAP1 mutations correlated with shorter progression-free survival. Overall, longitudinal liquid biopsy profiling provided valuable insights into lung cancer biology post-immunotherapy, potentially guiding personalized therapies and future drug development.
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Affiliation(s)
- Haolun Ding
- Department of Statistics and Finance, School of Management, University of Science and Technology of China, Hefei, Anhui, China
| | - Min Yuan
- Department of Health Data Science, Anhui Medical University, Hefei, Anhui, China.
| | - Yaning Yang
- Department of Statistics and Finance, School of Management, University of Science and Technology of China, Hefei, Anhui, China
| | - Xu Steven Xu
- Clinical Pharmacology and Quantitative Science, Genmab Inc, Princeton, NJ, USA.
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Chen W, Zhang L, Gao M, Zhang N, Wang R, Liu Y, Niu Y, Jia L. Role of tertiary lymphoid structures and B cells in clinical immunotherapy of gastric cancer. Front Immunol 2025; 15:1519034. [PMID: 39840050 PMCID: PMC11747648 DOI: 10.3389/fimmu.2024.1519034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/16/2024] [Indexed: 01/23/2025] Open
Abstract
Gastric cancer is a common malignant tumor of the digestive tract, and its treatment remains a significant challenge. In recent years, the role of various immune cells in the tumor microenvironment in cancer progression and treatment has gained increasing attention. Immunotherapy, primarily based on immune checkpoint inhibitors, has notably improved the prognosis of patients with gastric cancer; however, challenges regarding therapeutic efficacy persist. Histological features within the tumor microenvironment, such as tertiary lymphoid structures (TLSs), tumor-infiltrating lymphocytes, and the proportion of intratumoral stroma, are emerging as potentially effective prognostic factors. In gastric cancer, TLSs may serve as local immune hubs, enhancing the ability of immune cells to interact with and recognize tumor antigens, which is closely linked to the effectiveness of immunotherapy and improved survival rates in patients. However, the specific cell type driving TLS formation in tumors has not yet been elucidated. Mature TLSs are B-cell regions containing germinal centers. During germinal center formation, B cells undergo transformations to become mature cells with immune function, exerting anti-tumor effects. Therefore, targeting B cells within TLSs could provide new avenues for gastric cancer immunotherapy. This review, combined with current research on TLSs and B cells in gastric cancer, elaborates on the relationship between TLSs and B cells in the prognosis and immunotherapy of patients with gastric cancer, aiming to provide effective guidance for precise immunotherapy.
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Affiliation(s)
- Weiyi Chen
- Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Lingli Zhang
- College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia, China
| | - Man Gao
- Bayannur Clinical Medical College, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Ning Zhang
- Central Laboratory, Bayannur Hospital, Bayannur, Inner Mongolia, China
| | - Rumeng Wang
- Central Laboratory, Bayannur Hospital, Bayannur, Inner Mongolia, China
| | - Yang Liu
- Central Laboratory, Bayannur Hospital, Bayannur, Inner Mongolia, China
| | - Yan Niu
- Medical Experiment Center, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Lizhou Jia
- Central Laboratory, Bayannur Hospital, Bayannur, Inner Mongolia, China
- Medical Experiment Center, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
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Menon NA, Kumar CD, Ramachandran P, Blaize B, Gautam M, Cordani M, Lekha Dinesh Kumar. Small-molecule inhibitors of WNT signalling in cancer therapy and their links to autophagy and apoptosis. Eur J Pharmacol 2025; 986:177137. [PMID: 39551337 DOI: 10.1016/j.ejphar.2024.177137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 11/19/2024]
Abstract
Cancer represents an intricate and heterogeneous ailment that evolves from a multitude of epigenetic and genetic variations that disrupt normal cellular function. The WNT/β-catenin pathway is essential in maintaining the balance between cell renewal and differentiation in various tissues. Abnormal activation of this pathway can lead to uncontrolled cell growth and initiate cancer across a variety of tissues such as the colon, skin, liver, and ovary. It enhances characteristics that lead to cancer progression, including angiogenesis, invasion and metastasis. Processes like autophagy and apoptosis which regulate cell death and play a crucial role in maintaining cellular equilibrium are also intimately linked with WNT/ β-catenin pathway. Thus, targeting WNT pathway has become a key strategy in developing antitumor therapies. Employing small molecule inhibitors has emerged as a targeted therapy to improve the clinical outcome compared to conventional cancer treatments. Many strategies using small molecule inhibitors for modulating the WNT/β-catenin pathway, such as hindering WNT ligands' secretion or interaction, disrupting receptor complex, and blocking the nuclear translocation of β-catenin have been investigated. These interventions have shown promise in both preclinical and clinical settings. This review provides a comprehensive understanding of the role of WNT/β-catenin signalling pathway's role in cancer, emphasizing its regulation of autophagy and apoptosis. Our goal is to highlight the potential of specific small molecule inhibitors targeting this pathway, fostering the development of novel, tailored cancer treatments.
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Affiliation(s)
- Nayana A Menon
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Chethana D Kumar
- Department of Surgical ICU, Christian Medical College, IDA Scudder Road, Vellore, 632004, Tamil Nadu, India
| | - Pournami Ramachandran
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Britny Blaize
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Mridul Gautam
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040, Madrid, Spain.
| | - Lekha Dinesh Kumar
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India.
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40
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Menu Y. Photon-Counting CT: Virtual Study, Real Benefit. Radiology 2025; 314:e243329. [PMID: 39807979 DOI: 10.1148/radiol.243329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Affiliation(s)
- Yves Menu
- From the Department of Radiology, Gustave Roussy Cancer Campus, 114 Rue Edouard Vaillant, 94805 Villejuif, France
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41
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Moorman A, Benitez EK, Cambulli F, Jiang Q, Mahmoud A, Lumish M, Hartner S, Balkaran S, Bermeo J, Asawa S, Firat C, Saxena A, Wu F, Luthra A, Burdziak C, Xie Y, Sgambati V, Luckett K, Li Y, Yi Z, Masilionis I, Soares K, Pappou E, Yaeger R, Kingham TP, Jarnagin W, Paty PB, Weiser MR, Mazutis L, D'Angelica M, Shia J, Garcia-Aguilar J, Nawy T, Hollmann TJ, Chaligné R, Sanchez-Vega F, Sharma R, Pe'er D, Ganesh K. Progressive plasticity during colorectal cancer metastasis. Nature 2025; 637:947-954. [PMID: 39478232 PMCID: PMC11754107 DOI: 10.1038/s41586-024-08150-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/02/2024] [Indexed: 11/06/2024]
Abstract
As cancers progress, they become increasingly aggressive-metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3-5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming.
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Affiliation(s)
- Andrew Moorman
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elizabeth K Benitez
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA
| | - Francesco Cambulli
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- New York Genome Center, New York, NY, USA
| | - Qingwen Jiang
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ahmed Mahmoud
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Pharmacology Program, Weill Cornell Graduate School, New York, NY, USA
| | - Melissa Lumish
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Case Western Reserve University, Cleveland, OH, USA
| | - Saskia Hartner
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sasha Balkaran
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jonathan Bermeo
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Simran Asawa
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Canan Firat
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Asha Saxena
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Fan Wu
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anisha Luthra
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Cassandra Burdziak
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yubin Xie
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Tri-Institutional PhD Program in Computational Biology and Medicine, New York, NY, USA
| | - Valeria Sgambati
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kathleen Luckett
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA
| | - Yanyun Li
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Bristol Myers Squibb, Princeton, NJ, USA
| | - Zhifan Yi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ignas Masilionis
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kevin Soares
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Emmanouil Pappou
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - T Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - William Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Philip B Paty
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Martin R Weiser
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Linas Mazutis
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Julio Garcia-Aguilar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tal Nawy
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Travis J Hollmann
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Bristol Myers Squibb, Princeton, NJ, USA
| | - Ronan Chaligné
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Roshan Sharma
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Dana Pe'er
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Howard Hughes Medical Institute, Chevy Chase, MD, USA.
| | - Karuna Ganesh
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Lasota J, Kaczorowski M, Chłopek M, Miłek-Krupa J, Szczepaniak M, Ylaya K, Chodyna M, Iżycka-Świeszewska E, Scherping A, Czapiewski P, Dziuba I, Kato Y, Hałoń A, Kowalik A, Miettinen M. An immunohistochemical and molecular genetic study of 60 colorectal carcinoma brain metastases in pursuit of predictive biomarkers for cancer therapy. Hum Pathol 2025; 155:105717. [PMID: 39824298 DOI: 10.1016/j.humpath.2025.105717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 01/07/2025] [Accepted: 01/14/2025] [Indexed: 01/20/2025]
Abstract
Colorectal carcinoma brain metastases (n = 60) were studied using next-generation sequencing and immunohistochemistry. RAS and BRAF mutations were detected in 58.2% and 7.3% of cases, respectively. Patients with RAS- and BRAF-mutant tumors could potentially benefit from the treatment with inhibitors. TP53 mutations were detected in 69.1% of metastases. Moreover, altered p53 expression was seen in 91.2% of cases. APC mutations were present in 41.8% of tumors. Diffuse nuclear accumulation of β-catenin was seen in 10.2% of metastases, although only 1 CTNNB1 mutant was identified. Nevertheless, targeting p53 and Wnt/β-catenin pathways may have potential therapeutic implications. Casein kinase 1α1 expression indicating susceptibility to protein kinase inhibitors, was seen in 95% metastases including 10 with strong immunoreactivity. The immune checkpoint marker CD276, a promising target for immunotherapy, was present on tumor cells in 50.8% of metastases and on stromal cells in almost all cases. PRAME, another immunotherapy target, was expressed in 21.7% of tumors. HER2 membrane immunostaining detected in 13.3% of cases implicated potential treatment with HER2 inhibitors. Expression of SLFN11, a predictor of response to DNA-damaging chemotherapies, and a biomarker of sensitivity to PARP inhibitors was seen in 8.3% of tumors. In 6.7% of metastases loss or partial loss of MTAP expression suggested sensitivity to PRMT5 inhibitors. CD44v5 expressed in 35% of cases indicated potential therapeutic utility of anti-CD44v5 monoclonal antibody treatment. Identification of predictive biomarkers through genomic profiling and proteomic analyses is a crucial step toward individually tailored therapeutic regimens for patients with colorectal carcinoma brain metastases.
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Affiliation(s)
- Jerzy Lasota
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
| | - Maciej Kaczorowski
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA; Department of Clinical and Experimental Pathology, Wrocław Medical University, Wrocław, Poland
| | - Małgorzata Chłopek
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA; Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland
| | - Justyna Miłek-Krupa
- Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland
| | | | - Kris Ylaya
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
| | - Miłosz Chodyna
- Department of Pathology and Neuropathology, Medical University of Gdansk, Gdansk, Poland
| | - Ewa Iżycka-Świeszewska
- Department of Pathology and Neuropathology, Medical University of Gdansk, Gdansk, Poland
| | - Anna Scherping
- Institute of Pathology, University Hospital Bonn, Bonn, Germany
| | - Piotr Czapiewski
- Department of Pathology, Staedtisches Klinikum Dessau, Brandenburg Medical School Theodor Fontane, Dessau, Germany; Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Ireneusz Dziuba
- Department of Pathology, Faculty of Medicine, Academy of Silesia, Katowice, Poland
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Agnieszka Hałoń
- Department of Clinical and Experimental Pathology, Wrocław Medical University, Wrocław, Poland
| | - Artur Kowalik
- Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland; Division of Medical Biology, Institute of Biology Jan Kochanowski University, Kielce, Poland
| | - Markku Miettinen
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
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Nakamura Y, Ozaki H, Ueno M, Komatsu Y, Yuki S, Esaki T, Taniguchi H, Sunakawa Y, Yamaguchi K, Kato K, Denda T, Nishina T, Takahashi N, Satoh T, Yasui H, Satake H, Oki E, Kato T, Ohta T, Matsuhashi N, Goto M, Okano N, Ohtsubo K, Yamazaki K, Yamashita R, Iida N, Yuasa M, Bando H, Yoshino T. Targeted therapy guided by circulating tumor DNA analysis in advanced gastrointestinal tumors. Nat Med 2025; 31:165-175. [PMID: 39284955 PMCID: PMC11750700 DOI: 10.1038/s41591-024-03244-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 08/09/2024] [Indexed: 01/23/2025]
Abstract
Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.
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Affiliation(s)
- Yoshiaki Nakamura
- International Research Promotion Office, National Cancer Center Hospital East, Kashiwa, Japan
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroshi Ozaki
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Yoshito Komatsu
- Department of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Taito Esaki
- Department of Gastrointestinal and Medical Oncology, NHO Kyushu Cancer Center, Fukuoka, Japan
| | - Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center, Nagoya, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Tomohiro Nishina
- Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan
| | - Naoki Takahashi
- Department of Gastroenterology, Saitama Cancer Center, Ina, Japan
| | - Taroh Satoh
- Center for Cancer Genomics and Precision Medicine, Osaka University Hospital, Suita, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Hironaga Satake
- Cancer Treatment Center, Kansai Medical University Hospital, Hirakata, Japan
- Department of Medical Oncology, Kochi Medical School, Nankoku, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Kato
- Department of Surgery, NHO Osaka National Hospital, Osaka, Japan
| | - Takashi Ohta
- Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Japan
| | - Nobuhisa Matsuhashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Center for One Medicine Innovative Translational Research (COMIT), Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Japan
| | - Naohiro Okano
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Koushiro Ohtsubo
- Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Riu Yamashita
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Naoko Iida
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Mihoko Yuasa
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hideaki Bando
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
- Kindai University Faculty of Medicine, Osakasayama, Japan.
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44
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Berner AM, Murugaesu N. The Evolving Role of Genomics in Colorectal Cancer. Clin Oncol (R Coll Radiol) 2025; 37:103661. [PMID: 39536702 DOI: 10.1016/j.clon.2024.10.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 08/08/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
Approximately 75% of colorectal cancers (CRCs) harbour an identifiable driver mutation, 5% of which are heritable. These drivers have recognised implications for prognosis and therapy selection. In addition, potential germline mutations require investigations to inform testing of relatives, as well as surveillance for other malignancies. With increasing numbers of targeted drugs being approved, judicious testing is required to ensure sufficient tumour sample is available for testing and at the right point in the cancer pathway. Liquid biopsy with circulating tumour DNA (ctDNA) in the blood presents an exciting adjunct to tumour tissue testing for molecular drivers, as well as escalation and de-escalation of therapy. Here, we review the most frequent molecular alterations in CRC, how genomic testing should be integrated into the treatment pathway for CRC, and sources of further education.
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Affiliation(s)
- A M Berner
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6AU, UK
| | - N Murugaesu
- Guy's & St Thomas' NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UK; Genomics England, 1 Canada Square, London E14 5AB, UK.
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45
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Shi M, Yang Y, Huang N, Zeng D, Mo Z, Wang J, Zhang X, Liu R, Wang C, Rong X, Wu Z, Huang Q, Shang H, Tang J, Wang Z, Cai J, Huang G, Guan Y, Guo J, Mu Q, Wang J, Liao W. Genetic and microenvironmental evolution of colorectal liver metastases under chemotherapy. Cell Rep Med 2024; 5:101838. [PMID: 39631402 PMCID: PMC11722126 DOI: 10.1016/j.xcrm.2024.101838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 09/16/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024]
Abstract
Drug resistance limits the efficacy of chemotherapy for colorectal cancer liver metastasis (CRLM). However, the evolution of CRLM during drug treatment remains poorly elucidated. Multi-omics and treatment response data from 115 samples of 49 patients with CRLM undergoing bevacizumab (BVZ)-based chemotherapy show little difference in genomic alterations in 92% of cases, while remarkable differences are observed at the transcriptomic level. By decoupling intrinsic and acquired resistance, we find that hepatocyte and myeloid cell infiltration contribute to 38.5% and 23.1% of acquired resistance, respectively. Importantly, SMAD4 mutations and chr20q copy-number gain are associated with intrinsic chemoresistance. Gene interference experiments suggest that SMAD4R361H/C mutations confer BVZ and 5-fluorouracil (5-FU) resistance through STAT3 signaling. Notably, supplementing BVZ and 5-FU with the STAT3 inhibitor GB201 restores therapeutic efficacy in SMAD4R361H/C cancer cells. Our study uncovers the evolutionary dynamics of CRLM and its microenvironment during treatment and offers strategies to overcome drug resistance.
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Affiliation(s)
- Min Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China; Cancer Center, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China; Foshan Key Laboratory of Translational Medicine in Oncology, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China
| | - Yingxi Yang
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Na Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Dongqiang Zeng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China; Cancer Center, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China; Foshan Key Laboratory of Translational Medicine in Oncology, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China
| | - Zongchao Mo
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Jiao Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xiaomeng Zhang
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Ran Liu
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Chunlin Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xiaoxiang Rong
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhenzhen Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qiong Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Haixia Shang
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Jihong Tang
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Zhaojun Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jianan Cai
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Genjie Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yijin Guan
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jian Guo
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Quanhua Mu
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Jiguang Wang
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China; SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen 518000, P.R. China.
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China; Cancer Center, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China; Foshan Key Laboratory of Translational Medicine in Oncology, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China.
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Goffredo P, Troester A, Wolf JM, Rudser K, Church TR, Shaukat A. Proximal Polyps Are Associated With Higher Incidence of Colorectal Cancer: Analysis of the Minnesota Colon Cancer Control Study. Am J Gastroenterol 2024:00000434-990000000-01491. [PMID: 39688958 DOI: 10.14309/ajg.0000000000003256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 12/12/2024] [Indexed: 12/19/2024]
Abstract
INTRODUCTION Despite reports indicating that polyps proximal to the splenic flexure have higher rates of metachronous colorectal adenocarcinoma (CRC), the role of adenoma location on surveillance recommendations remains unclear. This study aimed to analyze the association between index polyp location and postcolonoscopy CRC among participants of the Minnesota Colon Cancer Control Study. METHODS The Minnesota Colon Cancer Control Study randomized 46,551 patients 50-80 years to usual care, annual, or biennial screening with fecal occult-blood testing. Screening was performed between 1976 and 1992. Positive fecal occult-blood testing was followed by colonoscopy. We analyzed participants whose colonoscopy revealed at least 1 adenoma. Patients were divided into those with at least 1 lesion proximal to the splenic flexure and those without. RESULTS Of 2,295 patients, 815 had proximal adenomas. The majority were men; mean age = 62 years at randomization, and 69 years at index polyp. There was a high rate of advanced adenomas: 44% ≥ 1 polyp ≥1 cm, 35% with villous histology, and 5% high-grade dysplasia. At 20 years, 87 patients had a CRC diagnosis, and the estimated cumulative incidence of CRC was 4.3%. Proximal adenomas had a higher risk of developing a postcolonoscopy CRC (subdistribution hazard ratio = 1.63, 95% confidence interval = 1.05-2.53, P = 0.03), which was attenuated after adjusting for polyp multiplicity in sensitivity analyses (subdistribution hazard ratio = 1.56, 95% confidence interval = 0.96-2.53, P = 0.07). DISCUSSION Although patients with proximal adenomas were found to have higher hazards of postcolonoscopy CRC, adjusting for polyp multiplicity attenuated the strength of association. Further research is warranted to determine whether polyp location should be factored in the determination of appropriate surveillance intervals.
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Affiliation(s)
- Paolo Goffredo
- Department of Surgery, Division of Colon & Rectal Surgery, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Alexander Troester
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jack M Wolf
- Division of Biostatistics & Health Data Science, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kyle Rudser
- Division of Biostatistics & Health Data Science, University of Minnesota, Minneapolis, Minnesota, USA
| | - Timothy R Church
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
- Division of Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota, USA
| | - Aasma Shaukat
- Division of Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Gastroenterology, New York University Langone Health, New York, New York, USA
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47
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Ros J, Ucha JM, Garcia-Galea E, Gomez P, Martini G, Balconi F, Comas R, Alonso V, Rodriguez M, Baraibar I, Salva F, Saoudi N, Alcaraz A, Garcia A, Tabernero J, Elez E. Real-World Data of Patients with BRAF V600E-Mutated Metastatic Colorectal Cancer Treated with Trifluridine/Tipiracil. Cancers (Basel) 2024; 16:4140. [PMID: 39766040 PMCID: PMC11674344 DOI: 10.3390/cancers16244140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND For patients with refractory metastatic colorectal cancer (mCRC), trifluridine/tipiracil (FTD-TPI) has been associated with a significant improvement in overall survival (OS). However, data are lacking regarding the activity of FTD-TPI in patients with BRAF-mutated mCRC. METHODS This retrospective, multicenter, international cohort included patients with BRAF-mutated mCRC treated with FTD-TPI in a real-life setting in Spain and Italy. Survival analysis was performed using Kaplan-Meier methods and Cox proportional hazard models and according to established prognostic groups: good prognosis characteristics (GPC; < 3 metastatic sites and time from metastases to FTD-TPI ≥ 18 months) and poor prognosis characteristics (PPC; ≥ 3 metastatic sites or time from metastases to FTD-TPI < 18 months). RESULTS In the 26 patients included, the median age was 61 years, 13 (50%) were female, and 20 (77%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Fourteen (56%) patients had right-sided tumors, six (23%) had microsatellite instability tumors, and thirteen (50%) had liver metastases. Median progression-free survival was 2.3 months (95% CI 2.0-3.2), and median OS (mOS) was 6.6 months (95% CI 4.4-12.0). mOS was 7.6 vs. 4.2 months (HR 1.64, 95% CI 0.65-4.10, p = 0.3) for GPC and PPC patients, respectively. Exploratory analyses identified ECOG as the only feature associated with survival. The most frequent grade 3-4 adverse events were neutropenia (8%), anemia (8%), and asthenia (4%). CONCLUSIONS Patients with BRAF mutant mCRC achieved modest benefits with FTD-TPI; however, patients with GPC and ECOG 0 achieved longer OS compared with those with PPC or ECOG 1-2, thus warranting further exploration in prospective cohorts.
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Affiliation(s)
- Javier Ros
- Medical Oncology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Jose Maria Ucha
- Medical Oncology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
| | | | - Pablo Gomez
- Medical Oncology, Miguel Servet Hospital, 50009 Zaragoza, Spain
| | - Giulia Martini
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Francesca Balconi
- Medical Oncology, University Hospital, University of Cagliari, 09124 Cagliari, Italy
| | - Raquel Comas
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Vicente Alonso
- Medical Oncology, Miguel Servet Hospital, 50009 Zaragoza, Spain
| | - Marta Rodriguez
- Medical Oncology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Iosune Baraibar
- Medical Oncology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Francesc Salva
- Medical Oncology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Nadia Saoudi
- Medical Oncology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | | | - Ariadna Garcia
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Elena Elez
- Medical Oncology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
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Chen Y, Zhu D, Yu Y, Chang W, Ye L, Feng Q, Xu P, Chen M, Ji M, Wei Y, Liu T, Xu J. VIC Regimen (Vemurafenib/Irinotecan/Cetuximab) Versus Bevacizumab Plus Chemotherapy as First-Line Treatment for BRAF V600E-Mutated Unresectable or Metastatic Colorectal Cancer in Asian Patients: A Prospective Cohort Study. Clin Colorectal Cancer 2024; 23:354-363.e4. [PMID: 38845274 DOI: 10.1016/j.clcc.2024.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/13/2024] [Accepted: 05/14/2024] [Indexed: 12/01/2024]
Abstract
BACKGROUND Colorectal cancers (CRC) with BRAF V600E mutation exhibit limited chemotherapy response and a poor prognosis. Safety and efficacy of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen in the first-line setting for patients with BRAF V600E-mutated CRC remain undetermined. METHODS In the prospective cohort study, the untreated, BRAF V600E-mutated, unresectable or metastatic CRC patients were enrolled. The VIC regimen and bevacizumab plus chemotherapy were compared in the first-line setting. The objective response rate (ORR), disease control rate (DCR), conversion resection rate, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS In the intent-to-treat analysis, 38 patients received VIC regimen and 40 received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 63.2% vs. 37.5%, P = .025; DCR: 94.7% vs. 75.0%, P = .019). The VIC regimen significantly outperformed bevacizumab plus chemotherapy in both PFS (11.9 vs. 7.7 months; hazard ratio [HR] = 0.51, 95% CI, 0.30-0.87; P = .010) and OS (25.3 vs. 14.6 months; HR = 0.43, 95% CI, 0.22-0.82; P = .011). In the VIC group, the conversion resection rate for liver metastases was 34.8% (8 of 23 patients), and for unresectable local CRC it was 54.5% (6 of 11 patients). The adverse events rates of Grade 3 to 4 were 34.2% and 32.5% for the VIC regimen and bevacizumab plus chemotherapy respectively. CONCLUSIONS Among Asian patients with BRAF V600E-mutated CRC, the VIC regimen showed favorable outcomes compared to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting.
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Affiliation(s)
- Yijiao Chen
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dexiang Zhu
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yiyi Yu
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Huadong Hospital, Fudan University, Shanghai, China
| | - Wenju Chang
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lechi Ye
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qingyang Feng
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Pingping Xu
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive
| | - Miao Chen
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Meiling Ji
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive
| | - Ye Wei
- Department of General Surgery, Huadong Hospital, Fudan University, Shanghai, China
| | - Tianshu Liu
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Jianmin Xu
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
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Liu M, Liu Q, Hu K, Dong Y, Sun X, Zou Z, Ji D, Liu T, Yu Y. Colorectal cancer with BRAF V600E mutation: Trends in immune checkpoint inhibitor treatment. Crit Rev Oncol Hematol 2024; 204:104497. [PMID: 39245296 DOI: 10.1016/j.critrevonc.2024.104497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 08/29/2024] [Accepted: 08/31/2024] [Indexed: 09/10/2024] Open
Abstract
Colorectal cancer (CRC) with BRAF V600E mutation presents a formidable scientific and clinical challenge due to its aggressive nature and poor response to standard therapeutic approaches. BRAF V600E mutation-induced conspicuous activation of the MAPK pathway contributes to the relentless tumor progression. Nevertheless, the efficacy of multi-targeted MAPK pathway inhibition remains suboptimal in clinical practice. Patients with high microsatellite instability (MSI-H) have shown favorable results with immune checkpoint inhibitors (ICIs). The combination of the MAPK pathway inhibition with ICIs has recently emerged as a promising regimen to improve clinical outcomes in the microsatellite stable (MSS) subgroup of BRAF V600E-mutant metastatic CRC patients. In this review, we elucidate the unique tumor biology of BRAF V600E-mutant CRC, with a particular focus on the immune features underlying the rationale for ICI treatments in the MSI-H and MSS subpopulations, then highlight the trends in clinical trials of the ICI therapy for BRAF V600E-mutant metastatic CRC.
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Affiliation(s)
- Mengling Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qing Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Keshu Hu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yu Dong
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xun Sun
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhiguo Zou
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Dingkun Ji
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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50
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Mo C, Chadha B, Kuang C. An Evolving Landscape: New Therapies for Metastatic Colorectal Cancer. Clin Colorectal Cancer 2024; 23:337-345. [PMID: 39332920 PMCID: PMC11608151 DOI: 10.1016/j.clcc.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 08/18/2024] [Accepted: 08/21/2024] [Indexed: 09/29/2024]
Abstract
Substantial progress is being made in the development of novel therapies directed against colorectal cancer. The discovery of various molecular markers and advances in tumor profiling have facilitated the development of new targeted agents and immunotherapy. Not only have these drugs improved progression-free survival and even overall survival in some cases, but their related outcomes have also raised questions as to how to best combine or sequence therapies for even greater efficacy. Furthermore, we are beginning to understand how these combination therapies may yield for greater therapeutic response for patients with microsatellite stable colorectal cancer for which there is much need for improvement. In this article, we review recent trial data and explore the outcomes of various targeted therapies and immunotherapies for patient with advanced colorectal cancer.
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Affiliation(s)
- Christiana Mo
- Department of Oncology, Montefiore Einstein, Bronx, NY; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY
| | - Bhawneet Chadha
- Department of Oncology, Montefiore Einstein, Bronx, NY; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY
| | - Chaoyuan Kuang
- Department of Oncology, Montefiore Einstein, Bronx, NY; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY.
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