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Zhang Y, Tong S, Wan L. Two first-generation KRAS inhibitor safety profiles: a disproportionality analysis of individual reports from the FDA adverse event reporting system. Expert Opin Drug Saf 2025:1-11. [PMID: 40289838 DOI: 10.1080/14740338.2025.2499219] [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: 01/07/2025] [Revised: 03/30/2025] [Accepted: 04/15/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND First-generation KRAS inhibitors, sotorasib and adagrasib, are approved for treating non-small cell lung cancer and colorectal cancer with specific KRAS mutations. This study analyzed data from FAERS database to evaluate adverse events (AEs) associated with KRAS inhibitors. RESEARCH DESIGN AND METHODS Four disproportionality analysis methods were applied to measure risk signals: reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multi-item gamma poisson shrinker (MGPS) algorithms. RESULTS Between Q2 2021 and Q1 2024, 5,580 AEs in 2,958 reports on sotorasib or adagrasib were identified. Most patients were 45 and above, with a median age of 67. After meeting four algorithms' criteria, sotorasib and adagrasib retained 43 and 18 disproportionate priority items (PTs), respectively. Common AEs were diarrhea, hepatotoxicity, and pneumonitis. Unexpected important AEs included pericardial effusion, colitis, and pancreatitis associated with sotorasib; seizure, encephalopathy, unresponsiveness to stimuli and disorientation with adagrasib. Most AEs emerged within the first month of treatment. The median time to onset was 50 days for sotorasib and 21 days for adagrasib. CONCLUSIONS Our research revealed potential new AE signals and provided a comprehensive safety profile of KRAS inhibitors, emphasizing the importance of careful monitoring and supportive care.
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Affiliation(s)
- Ying Zhang
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shuhua Tong
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Li Wan
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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2
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Yoon J, Moon H, Jeon Y, Choe S, Yoon H. Signature Gene Mutations in Colorectal Cancer: Potential Neoantigens for Cancer Vaccines. Int J Mol Sci 2025; 26:4559. [PMID: 40429703 DOI: 10.3390/ijms26104559] [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: 04/08/2025] [Revised: 05/07/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Colorectal cancer (CRC), the third most common cancer worldwide, is one of the deadliest cancers. CRC is known as a cold tumor, characterized by a low immune response that makes it difficult for immune cells to infiltrate and exhibits strong resistance to immunotherapy with checkpoint inhibition. This restricted response is largely attributed to signature gene mutations including mismatch repair (MMR) genes, KRAS, BRAF, APC, and TP53, which are also the main oncogenes in CRC. Mutated signature genes continuously upregulate abnormal signaling pathways, leading to excessive proliferation, cancer progression, and metastasis. Furthermore, it reorganizes the tumor microenvironment (TME) by recruiting immunosuppressive cells. However, the mutation can produce neoantigens that can provoke an immune response, making it a potential target for immunotherapy. In particular, cancer vaccines that leverage the strong neoantigenic properties of these mutations are considered promising for overcoming immune resistance and eliciting anti-tumor responses. In this review, we will describe signature gene mutations in CRC and focus on cancer vaccines targeting these mutations as potential therapies for CRC.
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Affiliation(s)
- Jaegoo Yoon
- Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon 14662, Republic of Korea
| | - Haeun Moon
- Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon 14662, Republic of Korea
| | - Yuna Jeon
- Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon 14662, Republic of Korea
| | - Soohyun Choe
- Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon 14662, Republic of Korea
- Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Republic of Korea
| | - Hyunho Yoon
- Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon 14662, Republic of Korea
- Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Republic of Korea
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3
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Miao R, Yu J, Kim RD. Targeting the KRAS Oncogene for Patients with Metastatic Colorectal Cancer. Cancers (Basel) 2025; 17:1512. [PMID: 40361439 PMCID: PMC12071034 DOI: 10.3390/cancers17091512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Revised: 04/27/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, with KRAS mutations occurring in approximately 40% of cases. These mutations drive tumorigenesis through the constitutive activation of key signaling pathways, such as RAS-RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR, contributing to therapeutic resistance and poor prognosis. Advances in molecular biology have led to significant breakthroughs, including the development of KRAS G12C inhibitors, such as sotorasib and adagrasib, which have shown promise in clinical trials. However, their efficacy is limited to a small subset of KRAS-mutant CRC, and resistance mechanisms often emerge through compensatory pathway activation. Combination strategies, including KRAS inhibitors with anti-EGFR agents, have been explored in trials like KRYSTAL-1 and CodeBreaK 300. Emerging research highlights the role of the tumor microenvironment in immune evasion and therapeutic resistance, offering opportunities for novel immunotherapy approaches, including KRAS neoantigen vaccines and adoptive T-cell therapy. Despite these advancements, challenges such as intratumoral heterogeneity, limited immune infiltration, and non-G12C KRAS mutations remain significant hurdles. This review provides a comprehensive overview of the molecular mechanisms, current advances and challenges, and future prospects in the management of KRAS-mutant CRC.
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Affiliation(s)
- Ruoyu Miao
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA;
| | - James Yu
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA;
| | - Richard D. Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA;
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4
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Zhou Y, Ding Y, Xu B, Fei H, Wang Z. Genetically druggable targets for MAPK-activated colorectal cancer by a two-sample mendelian randomization analysis. Sci Rep 2025; 15:12239. [PMID: 40210889 PMCID: PMC11986099 DOI: 10.1038/s41598-024-82567-5] [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: 02/18/2024] [Accepted: 12/06/2024] [Indexed: 04/12/2025] Open
Abstract
Colorectal cancer (CRC) is a significant worldwide health issue, ranking second in women and third in men. Predictions estimate a rise to 2.5 million cases by 2035, with CRC being the fourth deadliest cancer due to delayed diagnosis and the scarcity of effective treatment options. Over 60% of CRC cases involve MAPK-activated signal pathways, particularly driven by RAS oncogene mutations, which hinder treatment responses, making them 'undruggable.' This study conducts a two-sample Mendelian randomization protein quantitative trait loci (pQTL) analysis to investigate the causal association between plasma proteins and MAPK-activated CRCs. The study indicates that four plasma proteins-MHC class I polypeptide-related sequence B (MICB), complement C4A, C4B, and interleukin-21 (IL-21) are associated with an increased risk of MAPK-activated CRCs. These findings highlight the possibility of utilizing plasma proteins as therapeutic targets and diagnostic markers to advance the fight against CRCs, indicating promising results for more effective interventions. To ascertain and expand upon these discoveries, further research is imperative to fully harness the potential of these discoveries.
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Affiliation(s)
- Yuxuan Zhou
- Department of Gastrointestinal Surgery/Hernia Surgery, Jilin Province People's Hospital, No. 1183 Gongnong Road, Changchun, Jilin, China
| | - Yunlong Ding
- Department of Emergency General Surgery, Weifang People's Hospital, Weifang, Shandong, China
| | - Bangyue Xu
- Jilin Central General Hospital, Changchun, Jilin, China
| | - Hongyang Fei
- Department of Hepatobiliary and Pancreatic Surgery, Jilin Province People's Hospital, No. 1183 Gongnong Road, Changchun, Jilin, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery/Hernia Surgery, Jilin Province People's Hospital, No. 1183 Gongnong Road, Changchun, Jilin, China.
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5
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Rathod LS, Sakle NS, Mokale SN. KRAS inhibitors in drug resistance and potential for combination therapy. TUMORI JOURNAL 2025; 111:20-40. [PMID: 39506389 DOI: 10.1177/03008916241289206] [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] [Indexed: 11/08/2024]
Abstract
Kirsten Rat Sarcoma (KRAS) is a potent target for cancer therapy because it acts as a signaling hub, engaging in various signaling pathways and regulating a number of cellular functions like cell differentiation, proliferation, and survival. Recently, an emergency approval from the US-FDA has been issued for KRASG12C inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. However, clinical studies on covalent KRASG12C inhibitors have rapidly confronted resistance in patients. Many methods are being assessed to overcome this resistance, along with various combinatorial clinical studies that are in process. Moreover, because KRASG12D and KRASG12V are more common than KRASG12C, focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRASG12C inhibitors.
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6
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Zhan F, Guo Y, He L. NETosis Genes and Pathomic Signature: A Novel Prognostic Marker for Ovarian Serous Cystadenocarcinoma. JOURNAL OF IMAGING INFORMATICS IN MEDICINE 2024:10.1007/s10278-024-01366-6. [PMID: 39663319 DOI: 10.1007/s10278-024-01366-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/15/2024] [Accepted: 11/29/2024] [Indexed: 12/13/2024]
Abstract
To evaluate the prognostic significance and molecular mechanism of NETosis markers in ovarian serous cystadenocarcinoma (OSC), we constructed a machine learning-based pathomic model utilizing hematoxylin and eosin (H&E) slides. We analyzed 333 patients with OSC from The Cancer Genome Atlas for prognostic-related neutrophil extracellular trap formation (NETosis) genes through bioinformatics analysis. Pathomic features were extracted from 54 cases with complete pathological images, genetic matrices, and clinical information. Two pathomic prognostic models were constructed using support vector machine (SVM) and logistic regression (LR) algorithms. Additionally, we established a predictive scoring system that integrated pathomic scores based on the NETcluster subtypes and clinical signature. We identified four NETosis genes significantly correlated with OSC prognosis, which were functionally associated with immune response, somatic mutations, tumor invasion, and metastasis. Five robust pathomic features were selected for overall survival prediction. The LR and SVM pathomic models demonstrated strong predictive performance for the NETcluster subtype classification through five-fold cross-validation. Time-dependent ROC analysis revealed excellent prognostic capability of the LR pathomic model's score for the overall survival (AUC values of 0.658, 0.761, and 0.735 at 36, 48, and 60 months, respectively), further validated by Kaplan-Meier analysis. The expression levels of NETosis genes greatly affected OSC patients' prognoses. The pathomic analysis of H&E slide pathological images provides an effective approach for predicting both NETcluster subtype and overall survival in OSC patients.
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Affiliation(s)
- Feng Zhan
- College of Engineering, Fujian Jiangxia University, Fuzhou, Fujian, China
- School of Electronic Information Engineering, Taiyuan University of Science and Technology, Taiyuan, Shanxi, China
| | - Yina Guo
- School of Electronic Information Engineering, Taiyuan University of Science and Technology, Taiyuan, Shanxi, China
| | - Lidan He
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
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Xiao A, Li X, Wang C, Ye J, Fakih M. Updated survival outcome of regorafenib, ipilimumab, and nivolumab in refractory microsatellite stable non-liver metastatic colorectal cancer: A phase I nonrandomized clinical trial. Eur J Cancer 2024; 213:115111. [PMID: 39504677 DOI: 10.1016/j.ejca.2024.115111] [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: 06/18/2024] [Revised: 10/18/2024] [Accepted: 10/27/2024] [Indexed: 11/08/2024]
Abstract
BACKGROUND Combination regorafenib, ipilimumab, and nivolumab (RIN) was evaluated in a phase 1 nonrandomized study (NCT04362839) of refractory microsatellite stable (MSS) metastatic colorectal cancer. Promising antitumor activity was previously reported in the non-liver metastatic (NLM) population. This updated analysis describes long-term survival outcomes in the NLM cohort and highlights durable remissions with potential cure following completion of RIN therapy. METHODS Between May 2020 and January 2022, 39 patients with refractory MSS metastatic colorectal cancer were enrolled. Patients received RIN until progression, unacceptable toxicity, or completion at two years. The primary endpoint was recommended phase 2 dose (RP2D) selection. Secondary endpoints were safety, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) at the RP2D level. RESULTS 22 patients with refractory non-liver metastatic MSS colorectal cancer were treated at the RP2D of RIN. ORR was 36.4 % (8/22 patients), and median PFS was 5.0 months (95 % CI: 3-9). After a median follow-up of 42 months, the 1-, 2-, and 3-year PFS rates were 24.1 %, 24.1 %, and 19.3 % by RECIST. The median OS was 27.5 months (95 % CI: 14.0 to NE). At data cutoff, 6 patients had ongoing clinical benefit, including 3 responders who remain disease-free > 18 months after treatment completion. CONCLUSION With extended follow-up, RIN combination therapy demonstrated durable clinical benefit in a subset of patients with NLM MSS metastatic colorectal cancer, including potential cure in 3 responders who remain disease-free > 18 months after treatment completion.
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Affiliation(s)
- Annie Xiao
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
| | - Xiaochen Li
- Division of Biostatistics, Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
| | - Chongkai Wang
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
| | - Jian Ye
- Department of Immuno-oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA.
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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8
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Deng RZ, Zheng X, Lu ZL, Yuan M, Meng QC, Wu T, Tian Y. Effect of colorectal cancer stem cells on the development and metastasis of colorectal cancer. World J Gastrointest Oncol 2024; 16:4354-4368. [PMID: 39554751 PMCID: PMC11551631 DOI: 10.4251/wjgo.v16.i11.4354] [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: 07/23/2024] [Revised: 08/24/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role - immune checkpoints - and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Run-Zhi Deng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Xin Zheng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Zhong-Lei Lu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Ming Yuan
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Qi-Chang Meng
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Tao Wu
- Department of General Surgery, West China Hospital of Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Yu Tian
- Department of Thoracic Surgery, Yancheng No. 1 People’s Hospital, Affiliated Hospital of Nanjing University Medical School, The First People’s Hospital of Yancheng, Yancheng 224000, Jiangsu Province, China
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9
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Zuo WF, Pang Q, Zhu X, Yang QQ, Zhao Q, He G, Han B, Huang W. Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies. J Hematol Oncol 2024; 17:81. [PMID: 39232809 PMCID: PMC11375894 DOI: 10.1186/s13045-024-01601-1] [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: 07/04/2024] [Accepted: 08/20/2024] [Indexed: 09/06/2024] Open
Abstract
Heat shock proteins are essential molecular chaperones that play crucial roles in stabilizing protein structures, facilitating the repair or degradation of damaged proteins, and maintaining proteostasis and cellular functions. Extensive research has demonstrated that heat shock proteins are highly expressed in cancers and closely associated with tumorigenesis and progression. The "Hallmarks of Cancer" are the core features of cancer biology that collectively define a series of functional characteristics acquired by cells as they transition from a normal state to a state of tumor growth, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, the induction of angiogenesis, and the activation of invasion and metastasis. The pivotal roles of heat shock proteins in modulating the hallmarks of cancer through the activation or inhibition of various signaling pathways has been well documented. Therefore, this review provides an overview of the roles of heat shock proteins in vital biological processes from the perspective of the hallmarks of cancer and summarizes the small-molecule inhibitors that target heat shock proteins to regulate various cancer hallmarks. Moreover, we further discuss combination therapy strategies involving heat shock proteins and promising dual-target inhibitors to highlight the potential of targeting heat shock proteins for cancer treatment. In summary, this review highlights how targeting heat shock proteins could regulate the hallmarks of cancer, which will provide valuable information to better elucidate and understand the roles of heat shock proteins in oncology and the mechanisms of cancer occurrence and development and aid in the development of more efficacious and less toxic novel anticancer agents.
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Affiliation(s)
- Wei-Fang Zuo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qiwen Pang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xinyu Zhu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qian-Qian Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qian Zhao
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Gu He
- Department of Dermatology and Venereology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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10
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Fan H, Hu X, Cao F, Zhou L, Wen R, Shen H, Fu Y, Zhu X, Jia H, Liu Z, Wang G, Yu G, Chang W, Zhang W. WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer. NPJ Precis Oncol 2024; 8:144. [PMID: 39014007 PMCID: PMC11252267 DOI: 10.1038/s41698-024-00650-6] [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: 03/29/2024] [Accepted: 07/09/2024] [Indexed: 07/18/2024] Open
Abstract
Protein tyrosine phosphatase SHP2 activates RAS signaling, which is a novel target for colorectal cancer (CRC) therapy. However, SHP2 inhibitor monotherapy is ineffective for metastatic CRC and a combination therapy is required. In this study, we aimed to improve the antitumor efficacy of SHP2 inhibition and try to explore the resistance mechanism of SHP2 inhibitor. Results showed that WWP1 promoted the proliferation of CRC cells. Genetic or pharmacological inhibition of WWP1 enhanced the effect of SHP2 inhibitor in suppressing tumor growth in vitro and in vivo. WWP1 may mediate feedback reactivation of AKT signaling following SHP2 inhibition. Furthermore, nomogram models constructed with IHC expression of WWP1 and SHP2 greatly improved the accuracy of prognosis prediction for patients with CRC. Our findings indicate that WWP1 inhibitor I3C can synergize with SHP2 inhibitor and is expected to be a new strategy for clinical trials in treating advanced CRC patients.
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Affiliation(s)
- Hao Fan
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xuefei Hu
- Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China
| | - Fuao Cao
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Leqi Zhou
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Rongbo Wen
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hao Shen
- Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China
| | - Yating Fu
- Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China
| | - Xiaoming Zhu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hang Jia
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zixuan Liu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Guimin Wang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Guanyu Yu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
| | - Wenjun Chang
- Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China.
| | - Wei Zhang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
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11
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Zhang Y, Zhang Y, Song J, Cheng X, Zhou C, Huang S, Zhao W, Zong Z, Yang L. Targeting the "tumor microenvironment": RNA-binding proteins in the spotlight in colorectal cancer therapy. Int Immunopharmacol 2024; 131:111876. [PMID: 38493688 DOI: 10.1016/j.intimp.2024.111876] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/04/2024] [Accepted: 03/13/2024] [Indexed: 03/19/2024]
Abstract
Colorectal cancer (CRC) is the third most common cancer and has the second highest mortality rate among cancers. The development of CRC involves both genetic and epigenetic abnormalities, and recent research has focused on exploring the ex-transcriptome, particularly post-transcriptional modifications. RNA-binding proteins (RBPs) are emerging epigenetic regulators that play crucial roles in post-transcriptional events. Dysregulation of RBPs can result in aberrant expression of downstream target genes, thereby affecting the progression of colorectal tumors and the prognosis of patients. Recent studies have shown that RBPs can influence CRC pathogenesis and progression by regulating various components of the tumor microenvironment (TME). Although previous research on RBPs has primarily focused on their direct regulation of colorectal tumor development, their involvement in the remodeling of the TME has not been systematically reported. This review aims to highlight the significant role of RBPs in the intricate interactions within the CRC tumor microenvironment, including tumor immune microenvironment, inflammatory microenvironment, extracellular matrix, tumor vasculature, and CRC cancer stem cells. We also highlight several compounds under investigation for RBP-TME-based treatment of CRC, including small molecule inhibitors such as antisense oligonucleotides (ASOs), siRNAs, agonists, gene manipulation, and tumor vaccines. The insights gained from this review may lead to the development of RBP-based targeted novel therapeutic strategies aimed at modulating the TME, potentially inhibiting the progression and metastasis of CRC.
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Affiliation(s)
- Yiwei Zhang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China; Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China; Queen Mary School, Nanchang University, 330006 Nanchang, China
| | - Yujun Zhang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China; Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China
| | - Jingjing Song
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China; Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China; School of Ophthalmology and Optometry of Nanchang University, China
| | - Xifu Cheng
- School of Ophthalmology and Optometry of Nanchang University, China
| | - Chulin Zhou
- The Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Shuo Huang
- The Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Wentao Zhao
- The 3rd Clinical Department of China Medical University, 10159 Shenyang, China
| | - Zhen Zong
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China.
| | - Lingling Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China.
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12
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Iyer KK, Poel D, Miggelenbrink A, Kerkhof W, Janssen J, Bakkerus L, de Jong L, van den Hombergh E, Nagtegaal ID, Tauriello DVF, van Erp NP, Verheul HMW. High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids. BJC REPORTS 2024; 2:29. [PMID: 39516561 PMCID: PMC11523998 DOI: 10.1038/s44276-024-00042-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/11/2023] [Accepted: 01/20/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Most tyrosine kinase inhibitors (TKIs) have failed in clinical trials for metastatic colorectal cancer (mCRC). To leverage the additional lower-affinity targets that most TKIs have, high-dose regimens that trigger efficacy are explored. Here, we studied unprecedented drug exposure-response relationships in vitro using mCRC patient-derived tumour organoids (PDTOs). METHODS We investigated the cytotoxic anti-tumour effect of high-dose, short-term (HDST) TKI treatment on 5 PDTOs. Sunitinib, cediranib and osimertinib were selected based on favourable physicochemical and pharmacokinetic properties. Intra-tumoroid TKI concentrations were measured using a clinically validated LC/MS-MS method. Cell death was determined using an enzyme activity assay, immunofluorescent staining and western blotting. RESULTS Most PDTOs tested were sensitive to sunitinib and cediranib, but all to osimertinib. Furthermore, HDST osimertinib treatment effectively blocks organoid growth. This treatment led to markedly elevated intra-tumoroid TKI concentrations, which correlated with PDTO sensitivity. Mechanistically, HDST osimertinib treatment induced apoptosis in treated PDTOs. CONCLUSION Our work provides a better understanding of TKI exposure vs response and can be used to determine patient-specific sensitivity. Additionally, these results may guide both mechanistic elucidation in organotypic translational models and the translation of target drug exposure to clinical dosing strategies. Moreover, HDST osimertinib treatment warrants clinical exploration for mCRC.
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Affiliation(s)
- Kirti K Iyer
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Dennis Poel
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Anne Miggelenbrink
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Wouter Kerkhof
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Jorien Janssen
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Lotte Bakkerus
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Loek de Jong
- Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Erik van den Hombergh
- Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Daniele V F Tauriello
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Medical Oncology, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Nielka P van Erp
- Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands.
- Department of Medical Oncology, Erasmus Medical Centre, Rotterdam, The Netherlands.
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13
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Ozmen E, Demir TD, Ozcan G. Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer. Front Mol Biosci 2024; 11:1340124. [PMID: 38562556 PMCID: PMC10982390 DOI: 10.3389/fmolb.2024.1340124] [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: 11/17/2023] [Accepted: 01/31/2024] [Indexed: 04/04/2024] Open
Abstract
Enhanced knowledge of the interaction of cancer cells with their environment elucidated the critical role of tumor microenvironment in tumor progression and chemoresistance. Cancer-associated fibroblasts act as the protagonists of the tumor microenvironment, fostering the metastasis, stemness, and chemoresistance of cancer cells and attenuating the anti-cancer immune responses. Gastric cancer is one of the most aggressive cancers in the clinic, refractory to anti-cancer therapies. Growing evidence indicates that cancer-associated fibroblasts are the most prominent risk factors for a poor tumor immune microenvironment and dismal prognosis in gastric cancer. Therefore, targeting cancer-associated fibroblasts may be central to surpassing resistance to conventional chemotherapeutics, molecular-targeted agents, and immunotherapies, improving survival in gastric cancer. However, the heterogeneity in cancer-associated fibroblasts may complicate the development of cancer-associated fibroblast targeting approaches. Although single-cell sequencing studies started dissecting the heterogeneity of cancer-associated fibroblasts, the research community should still answer these questions: "What makes a cancer-associated fibroblast protumorigenic?"; "How do the intracellular signaling and the secretome of different cancer-associated fibroblast subpopulations differ from each other?"; and "Which cancer-associated fibroblast subtypes predominate specific cancer types?". Unveiling these questions can pave the way for discovering efficient cancer-associated fibroblast targeting strategies. Here, we review current knowledge and perspectives on these questions, focusing on how CAFs induce aggressiveness and therapy resistance in gastric cancer. We also review potential therapeutic approaches to prevent the development and activation of cancer-associated fibroblasts via inhibition of CAF inducers and CAF markers in cancer.
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Affiliation(s)
- Ece Ozmen
- Koç University Graduate School of Health Sciences, Istanbul, Türkiye
| | - Tevriz Dilan Demir
- Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Türkiye
| | - Gulnihal Ozcan
- Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Türkiye
- Department of Medical Pharmacology, Koç University School of Medicine, Istanbul, Türkiye
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14
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Yang Z, Zhang X, Bai X, Xi X, Liu W, Zhong W. Anti-angiogenesis in colorectal cancer therapy. Cancer Sci 2024; 115:734-751. [PMID: 38233340 PMCID: PMC10921012 DOI: 10.1111/cas.16063] [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: 09/18/2023] [Revised: 11/16/2023] [Accepted: 12/16/2023] [Indexed: 01/19/2024] Open
Abstract
The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.
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Affiliation(s)
- Zhenni Yang
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
- Department of Gastroenterology and HepatologyXing'an League People's HospitalXing'an LeagueChina
| | - Xuqian Zhang
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
- Department of Gastroenterology and HepatologyChina Aerospace Science and Industry CorporationBeijingChina
| | - Xiaozhe Bai
- Department of Gastroenterology and HepatologyXing'an League People's HospitalXing'an LeagueChina
| | - Xiaonan Xi
- State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Wentian Liu
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
| | - Weilong Zhong
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
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15
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Wei Y, Zhao X, Tang H, Ma J, Wang Y, Li L. SIM2: Its Prognostic Significance and Oncogenic Role in Endometrial Carcinoma. Onco Targets Ther 2024; 17:45-61. [PMID: 38292061 PMCID: PMC10826595 DOI: 10.2147/ott.s440788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 01/09/2024] [Indexed: 02/01/2024] Open
Abstract
Background Endometrial carcinoma ranks as the second most widespread malignancy affecting the reproductive system in females. Effective prognostic biomarkers are required to further improve survival rates for patients. Single-minded homolog 2 (SIM2) is known to participate in neurogenesis as a transcription factor. However, the potential role of SIM2 in endometrial carcinoma remains elusive. Methods Multiple public databases, including TIMER2.0, GEIPA2, UALCAN, LinkedOmics, BioGRID, DAVID and cBioPortal, were used to investigate SIM2 mRNA expression, SIM2-associated genes, PPI network, functional enrichment analysis, SIM2 gene alterations and methylation. The association between SIM2 expression and immune cell infiltrates was explored using GSVA. The effects of gene alterations and methylation on patient survival and CD8+T infiltration were examined using GSCA. Moreover, the prognostic potential of SIM2 was evaluated using COX regression, ROC curves and a nomogram model. Finally, the differential expression and function of SIM2 in UCEC were explored using qPCR, WB, CCK8 and Transwell assays. Results Our findings revealed the heightened expression of SIM2 in endometrial carcinoma, and that its DNA methylation and CNV alterations were correlated with immune infiltration and patients' prognosis. Additionally, functional enrichment revealed the involvement of SIM2 in transcription regulation and signal transduction. Moreover, we performed cell-based experiments to corroborate the oncogenic function of SIM2 in facilitating cell proliferation, migration and invasion. Conclusion Collectively, these results suggest that SIM2 holds promise as both a potential prognostic indicator and a viable treatment target for endometrial carcinoma.
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Affiliation(s)
- Yunfang Wei
- Department of Obstetrics & Gynecology, Shanghai Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, People’s Republic of China
| | - Xianlei Zhao
- Department of Obstetrics & Gynecology, Shanghai Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, People’s Republic of China
| | - Hong Tang
- Department of Obstetrics & Gynecology, Shanghai Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, People’s Republic of China
| | - Jin Ma
- Department of Obstetrics & Gynecology, Shanghai Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, People’s Republic of China
| | - Yongfeng Wang
- Department of Obstetrics & Gynecology, Shanghai Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, People’s Republic of China
| | - Linxia Li
- Department of Obstetrics & Gynecology, Shanghai Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, People’s Republic of China
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16
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Zhang RY, Cheng K, Huang ZY, Zhang XS, Li Y, Sun X, Yang XQ, Hu YG, Hou XL, Liu B, Chen W, Fan JX, Zhao YD. M1 macrophage-derived exosome for reprograming M2 macrophages and combining endogenous NO gas therapy with enhanced photodynamic synergistic therapy in colorectal cancer. J Colloid Interface Sci 2024; 654:612-625. [PMID: 37862809 DOI: 10.1016/j.jcis.2023.10.054] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/19/2023] [Accepted: 10/12/2023] [Indexed: 10/22/2023]
Abstract
Reprogramming immunosuppressive M2 macrophages into M1 macrophages in tumor site provides a new strategy for the immunotherapy of colorectal cancer. In this study, M1 macrophage-derived exosome nanoprobe (M1UC) with Ce6-loaded upconversion material is designed to enhance the photodynamic performance of Ce6 while reprogramming M2 macrophages at tumor site and producing NO gas for three-mode synergistic therapy. Under the excitation of near-infrared light at 808 nm, the probe can generate 660 nm up-conversion fluorescence, which enables the photosensitizer Ce6 to produce ROS efficiently. In addition, the probe leads the production of NO by nitric oxide synthase on exosomes. Confocal laser and flow cytometry results show that M1UC probe reprograms M2 macrophages into M1 macrophages with an efficiency of 95.12%. The cell experiments show that the apoptosis rate of the three-mode synergistic therapy group is 78.8%, and the therapeutic effect is significantly higher than those of the other single treatment groups. In vivo experiments results show that M1UC probes maximally gather at the tumor site after 12 h of intravenous injection in orthotopic colorectal cancer mice. After 808 nm laser irradiation, the survival rate of mice is 100% and the recurrence rate was 0 within 60 d, and the therapeutic effect is significantly higher than those of other single treatment groups, which is also confirmed by immunohistochemistry. This M1 macrophage-derived exosome nanoplatform which is based on the three modes of immunotherapy, gas therapy and photodynamic therapy, provides a new design idea for the diagnosis and treatment of deep tumors.
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Affiliation(s)
- Ruo-Yun Zhang
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China; School of Bioengineering and Health, Wuhan Textile University, Wuhan 430200, Hubei, PR China; State Key Laboratory of New Textile Materials and Advanced Processing Technologies, Wuhan Textile University, Wuhan 430200, Hubei, PR China
| | - Kai Cheng
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China
| | - Zhuo-Yao Huang
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China
| | - Xiao-Shuai Zhang
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China; Basic Medical Laboratory, General Hospital of Central Theater Command, Wuhan 430081, Hubei, PR China
| | - Yong Li
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China
| | - Xing Sun
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China
| | - Xiao-Quan Yang
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China
| | - Yong-Guo Hu
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China
| | - Xiao-Lin Hou
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China
| | - Bo Liu
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China
| | - Wei Chen
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China
| | - Jin-Xuan Fan
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China.
| | - Yuan-Di Zhao
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, PR China.
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17
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Kwantwi LB. Genetic alterations shape innate immune cells to foster immunosuppression and cancer immunotherapy resistance. Clin Exp Med 2023; 23:4289-4296. [PMID: 37910258 DOI: 10.1007/s10238-023-01240-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 10/26/2023] [Indexed: 11/03/2023]
Abstract
Cancer immunotherapy, particularly immune checkpoint inhibitors, has opened a new avenue for cancer treatment following the durable clinical benefits. Despite the clinical successes across several cancer types, primary or acquired resistance might eventually lead to cancer progression in patients with clinical responses. Hence, to broaden the clinical applicability of these treatments, a detailed understanding of the mechanisms limiting the efficacy of cancer immunotherapy is needed. Evidence provided thus far has implicated immunosuppressive innate immune cells infiltrating the tumor microenvironment as key players in immunotherapy resistance. According to the available data, genetic alterations can shape the innate immune response to promote immunotherapy resistance and tumor progression. Herein, this review has discussed the current understanding of the underlying mechanisms where genetic alterations modulate the innate immune milieu to drive immunosuppression and immunotherapy resistance.
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Affiliation(s)
- Louis Boafo Kwantwi
- Department of Pathology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
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18
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Yang Z, Luo J, Zhang M, Zhan M, Bai Y, Yang Y, Wang W, Lu L. TMSB4X: A novel prognostic marker for non-small cell lung cancer. Heliyon 2023; 9:e21505. [PMID: 38027718 PMCID: PMC10663839 DOI: 10.1016/j.heliyon.2023.e21505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 10/18/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Non-small cell lung cancer (NSCLC), as the main type of lung cancer, has a long history of high incidence and mortality. Despite the continuous updates to the American Joint Committee on Cancer (AJCC) staging system, which adapt to evolving treatment modalities and diagnostic advancements, it is evident that patients at the same stage exhibit varying prognoses. The heterogeneity of tumors underscores the need for molecular diagnostics to assume a pivotal role in tumor staging and patient stratification. In our investigation, we meticulously analyzed the data of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, incorporating clinical patients and scrutinizing pathological specimens. Through this comprehensive approach, we established a correlation between the expression of the Thymosin beta 4 X-linked (TMSB4X) gene and poorer disease-free survival (DFS) and overall survival (OS) post-surgery. Compared to the TMSB4X positive expression group, patients in the negative expression group had a better prognosis, with longer DFS (median disease-free survival (median DFS): 16.2 months vs. 11.3 months, P = 0.032) and OS (median overall survival (mOS): 29.8 months vs. 18.5 months, P = 0.033). Furthermore, our findings suggest that TMSB4X may facilitate immune evasion in non-small cell lung cancer cells by influencing the activation of infiltrating dendritic cells (DCs) in tumor infiltrating immune cells (TIICs) (R = 0.27, P = 4.8E+08). In summary, TMSB4X emerges as an unfavorable prognostic factor for NSCLC, potentially modulating the tumor immune microenvironment through its regulatory impact on dendritic cell function, thus facilitating tumor immune escape.
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Affiliation(s)
- Ze Yang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, Guangdong, China
- The Second Affiliated Hospital of Zunyi Medical University, Zun Yi, Gui Zhou, China
| | - Jihang Luo
- Affiliated Hospital of Zunyi Medical University, Zun Yi, Gui Zhou, China
| | - Mengmei Zhang
- Zunyi Medical and Pharmaceutical College, Zun Yi, Gui Zhou, China
| | - Meixiao Zhan
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, Guangdong, China
| | - Yuju Bai
- The Second Affiliated Hospital of Zunyi Medical University, Zun Yi, Gui Zhou, China
| | - Yi Yang
- The Second Affiliated Hospital of Zunyi Medical University, Zun Yi, Gui Zhou, China
| | - Wei Wang
- Department of Pulmonary and Critical Care Medicine, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, Guangdong, China
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, Guangdong, China
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Jagadeeshan S, Novoplansky OZ, Cohen O, Kurth I, Hess J, Rosenberg AJ, Grandis JR, Elkabets M. New insights into RAS in head and neck cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188963. [PMID: 37619805 PMCID: PMC11815531 DOI: 10.1016/j.bbcan.2023.188963] [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: 06/29/2023] [Revised: 08/15/2023] [Accepted: 08/15/2023] [Indexed: 08/26/2023]
Abstract
RAS genes are known to be dysregulated in cancer for several decades, and substantial effort has been dedicated to develop agents that reduce RAS expression or block RAS activation. The recent introduction of RAS inhibitors for cancer patients highlights the importance of comprehending RAS alterations in head and neck cancer (HNC). In this regard, we examine the published findings on RAS alterations and pathway activations in HNC, and summarize their role in HNC initiation, progression, and metastasis. Specifically, we focus on the intrinsic role of mutated-RAS on tumor cell signaling and its extrinsic role in determining tumor-microenvironment (TME) heterogeneity, including promoting angiogenesis and enhancing immune escape. Lastly, we summarize the intrinsic and extrinsic role of RAS alterations on therapy resistance to outline the potential of targeting RAS using a single agent or in combination with other therapeutic agents for HNC patients with RAS-activated tumors.
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Affiliation(s)
- Sankar Jagadeeshan
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel.
| | - Ofra Z Novoplansky
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel.
| | - Oded Cohen
- Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel; Department of Otolaryngology- Head and Neck Surgery and Oncology, Soroka Medical Center, Beersheva, Israel.
| | - Ina Kurth
- Division of Radiooncology-Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Jochen Hess
- Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany; Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
| | - Ari J Rosenberg
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA.
| | - Jennifer R Grandis
- Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, CA, USA.
| | - Moshe Elkabets
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel.
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20
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Zhong Y, Yang K, Qin X, Luo R, Wang H. Impact of Molecular Status on Cytoreductive Surgery for Peritoneal Metastases from Colorectal Cancer. Clin Colon Rectal Surg 2023; 36:415-422. [PMID: 37795471 PMCID: PMC10547537 DOI: 10.1055/s-0043-1767705] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023]
Abstract
Colorectal cancer peritoneal metastases (CRC-PM) are present in 5 to 15% of instances of CRC, and the overall survival (OS) of patients with CRC-PM is much lower than that of patients with other isolated metastatic locations. In recent years, the introduction of cytoreductive surgery (CRS) in conjunction with hyperthermic intraperitoneal chemotherapy has resulted in a significant improvement in CRC-PM patients' OS. Despite this, a significant proportion of CRS patients continue to suffer complications of grades III to V or even die during the perioperative period. Early diagnosis, optimization of patient selection criteria, and refining of individualized combination therapy are necessary for these patients. In this review, we evaluate studies examining the relationship between molecular status and CRS in CRC-PM. Our objective is to gain a comprehensive understanding of how the altered molecular status of CRC-PM impacts CRS, which could increase the likelihood of tailored therapy in the future.
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Affiliation(s)
- Yun Zhong
- Department of Colorectal Surgery, Sun Yat-sen University, The Sixth Affiliated Hospital, Guangzhou, China
- Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Material Conversion and Evaluation Engineering Technology Research Center of Guangdong Province, Guangzhou, China
- Institute of Biomedical Innovation and Laboratory of Regenerative Medicine and Biomaterials, Guangzhou, China
| | - Keli Yang
- Department of Colorectal Surgery, Sun Yat-sen University, The Sixth Affiliated Hospital, Guangzhou, China
- Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Material Conversion and Evaluation Engineering Technology Research Center of Guangdong Province, Guangzhou, China
- Institute of Biomedical Innovation and Laboratory of Regenerative Medicine and Biomaterials, Guangzhou, China
| | - Xiusen Qin
- Department of Colorectal Surgery, Sun Yat-sen University, The Sixth Affiliated Hospital, Guangzhou, China
- Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Material Conversion and Evaluation Engineering Technology Research Center of Guangdong Province, Guangzhou, China
- Institute of Biomedical Innovation and Laboratory of Regenerative Medicine and Biomaterials, Guangzhou, China
| | - Rui Luo
- Department of Colorectal Surgery, Sun Yat-sen University, The Sixth Affiliated Hospital, Guangzhou, China
- Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Material Conversion and Evaluation Engineering Technology Research Center of Guangdong Province, Guangzhou, China
- Institute of Biomedical Innovation and Laboratory of Regenerative Medicine and Biomaterials, Guangzhou, China
| | - Hui Wang
- Department of Colorectal Surgery, Sun Yat-sen University, The Sixth Affiliated Hospital, Guangzhou, China
- Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Material Conversion and Evaluation Engineering Technology Research Center of Guangdong Province, Guangzhou, China
- Institute of Biomedical Innovation and Laboratory of Regenerative Medicine and Biomaterials, Guangzhou, China
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21
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Zhu X, Li S. Nanomaterials in tumor immunotherapy: new strategies and challenges. Mol Cancer 2023; 22:94. [PMID: 37312116 PMCID: PMC10262535 DOI: 10.1186/s12943-023-01797-9] [Citation(s) in RCA: 90] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 05/31/2023] [Indexed: 06/15/2023] Open
Abstract
Tumor immunotherapy exerts its anti-tumor effects by stimulating and enhancing immune responses of the body. It has become another important modality of anti-tumor therapy with significant clinical efficacy and advantages compared to chemotherapy, radiotherapy and targeted therapy. Although various kinds of tumor immunotherapeutic drugs have emerged, the challenges faced in the delivery of these drugs, such as poor tumor permeability and low tumor cell uptake rate, had prevented their widespread application. Recently, nanomaterials had emerged as a means for treatment of different diseases due to their targeting properties, biocompatibility and functionalities. Moreover, nanomaterials possess various characteristics that overcome the defects of traditional tumor immunotherapy, such as large drug loading capacity, precise tumor targeting and easy modification, thus leading to their wide application in tumor immunotherapy. There are two main classes of novel nanoparticles mentioned in this review: organic (polymeric nanomaterials, liposomes and lipid nanoparticles) and inorganic (non-metallic nanomaterials and metallic nanomaterials). Besides, the fabrication method for nanoparticles, Nanoemulsions, was also introduced. In summary, this review article mainly discussed the research progress of tumor immunotherapy based on nanomaterials in the past few years and offers a theoretical basis for exploring novel tumor immunotherapy strategies in the future.
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Affiliation(s)
- Xudong Zhu
- Department of General Surgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, 110042, People's Republic of China
| | - Shenglong Li
- Second Ward of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, 110042, People's Republic of China.
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22
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Li A, Li X, Zou J, Zhuo X, Chen S, Chai X, Gai C, Xu W, Zhao Q, Zou Y. SOS1-inspired hydrocarbon-stapled peptide as a pan-Ras inhibitor. Bioorg Chem 2023; 135:106500. [PMID: 37003134 DOI: 10.1016/j.bioorg.2023.106500] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/22/2023] [Accepted: 03/23/2023] [Indexed: 04/03/2023]
Abstract
Blocking the interaction between Ras and Son of Sevenless homolog 1 (SOS1) has been an attractive therapeutic strategy for treating cancers involving oncogenic Ras mutations. K-Ras mutation is the most common in Ras-driven cancers, accounting for 86%, with N-Ras mutation and H-Ras mutation accounting for 11% and 3%, respectively. Here, we report the design and synthesis of a series of hydrocarbon-stapled peptides to mimic the alpha-helix of SOS1 as pan-Ras inhibitors. Among these stapled peptides, SSOSH-5 was identified to maintain a well-constrained alpha-helical structure and bind to H-Ras with high affinity. SSOSH-5 was furthermore validated to bind with Ras similarly to the parent linear peptide through structural modeling analysis. This optimized stapled peptide was proven to be capable of effectively inhibiting the proliferation of pan-Ras-mutated cancer cells and inducing apoptosis in a dose-dependent manner by modulating downstream kinase signaling. Of note, SSOSH-5 exhibited a high capability of crossing cell membranes and strong proteolytic resistance. We demonstrated that the peptide stapling strategy is a feasible approach for developing peptide-based pan-Ras inhibitors. Furthermore, we expect that SSOSH-5 can be further characterized and optimized for the treatment of Ras-driven cancers.
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Affiliation(s)
- Anpeng Li
- School of Pharmacy, Naval Medical University, Shanghai, PR China; 92805 Military Hospital, Qingdao, PR China
| | - Xiang Li
- School of Pharmacy, Naval Medical University, Shanghai, PR China
| | - Jihua Zou
- School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, PR China
| | - Xiaobin Zhuo
- School of Pharmacy, Naval Medical University, Shanghai, PR China
| | - Shuai Chen
- School of Pharmacy, Naval Medical University, Shanghai, PR China
| | - Xiaoyun Chai
- School of Pharmacy, Naval Medical University, Shanghai, PR China
| | - Conghao Gai
- School of Pharmacy, Naval Medical University, Shanghai, PR China
| | - Weiheng Xu
- School of Pharmacy, Naval Medical University, Shanghai, PR China.
| | - Qingjie Zhao
- School of Pharmacy, Naval Medical University, Shanghai, PR China.
| | - Yan Zou
- School of Pharmacy, Naval Medical University, Shanghai, PR China.
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23
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Nanomaterials: Breaking through the bottleneck of tumor immunotherapy. Int J Biol Macromol 2023; 230:123159. [PMID: 36610572 DOI: 10.1016/j.ijbiomac.2023.123159] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/23/2022] [Accepted: 01/02/2023] [Indexed: 01/06/2023]
Abstract
Immunotherapy exerts its excellent anti-tumor effects by stimulating and enhancing the immune response of the body, and has become another important class of anti-tumor therapy besides chemotherapy, targeted therapy and radiotherapy. Various types of immunotherapeutic drugs have gained their clinical values, but the in vivo delivery of drugs still faces many challenges, such as poor tumor permeability and low tumor cell uptake rate. In recent years, owing to highly targeting properties, better biocompatibility, and easy functionalization, nanomaterials have been widely applicated in tumor treatment, especially in tumor immunotherapy. Furthermore, nanomaterials have large drug loading capacity, strong tumor targeting and easy modification, which can effectively overcome the drawbacks of traditional immunotherapy. This paper reviews the progress of nanomaterial-based tumor immunotherapy in recent years and provides a theoretical basis for exploring new nanomaterial-based tumor immunotherapy strategies.
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24
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Ma SX, Li L, Cai H, Guo TK, Zhang LS. Therapeutic challenge for immunotherapy targeting cold colorectal cancer: A narrative review. World J Clin Oncol 2023; 14:81-88. [PMID: 36908678 PMCID: PMC9993140 DOI: 10.5306/wjco.v14.i2.81] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/13/2022] [Accepted: 02/07/2023] [Indexed: 02/21/2023] Open
Abstract
Cold colorectal tumors are not likely to trigger a robust immune response and tend to suppress the immune response. There may be three reasons. First, the complex tumor microenvironment of cold colorectal cancer (CRC) leads to tolerance and clearance of immunotherapy. Second, the modification and concealment of tumor-specific targets in cold CRC cause immune escape and immune response interruption. Finally, the difference in number and function of immune cell subsets in patients with cold CRC makes them respond poorly to immunotherapy. Therefore, we can only overcome the challenges in immunotherapy of cold CRC through in-depth research and understanding the changes and mechanisms in the above three aspects of cold CRC.
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Affiliation(s)
- Shi-Xun Ma
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
| | - Li Li
- Scientific Research Division, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hui Cai
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
| | - Tian-Kang Guo
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
| | - Lei-Sheng Zhang
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
- Key Laboratory of Radiation Technology and Biophysics, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui Province, China
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25
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Liu X, Xin Z, Wang K. Patient-derived xenograft model in colorectal cancer basic and translational research. Animal Model Exp Med 2023; 6:26-40. [PMID: 36543756 PMCID: PMC9986239 DOI: 10.1002/ame2.12299] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 11/22/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most popular malignancies globally, with 930 000 deaths in 2020. The evaluation of CRC-related pathogenesis and the discovery of potential therapeutic targets will be meaningful and helpful for improving CRC treatment. With huge efforts made in past decades, the systematic treatment regimens have been applied to improve the prognosis of CRC patients. However, the sensitivity of CRC to chemotherapy and targeted therapy is different from person to person, which is an important cause of treatment failure. The emergence of patient-derived xenograft (PDX) models shows great potential to alleviate the straits. PDX models possess similar genetic and pathological characteristics as the features of primary tumors. Moreover, PDX has the ability to mimic the tumor microenvironment of the original tumor. Thus, the PDX model is an important tool to screen precise drugs for individualized treatment, seek predictive biomarkers for prognosis supervision, and evaluate the unknown mechanism in basic research. This paper reviews the recent advances in constructed methods and applications of the CRC PDX model, aiming to provide new knowledge for CRC basic research and therapeutics.
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Affiliation(s)
- Xiaofeng Liu
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Zechang Xin
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Kun Wang
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
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26
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Li W, Chen W, Wang J, Zhao G, Chen L, Wan Y, Luo Q, Li W, Huang H, Li W, Li W, Yang Y, Chen D, Su Q. A PDX model combined with CD-DST assay to evaluate the antitumor properties of KRpep-2d and oxaliplatin in KRAS (G12D) mutant colorectal cancer. Heliyon 2022; 8:e12518. [PMID: 36590511 PMCID: PMC9800201 DOI: 10.1016/j.heliyon.2022.e12518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/20/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Patient-derived xenograft (PDX) models are more faithful in maintaining the characteristics of human tumors than cell lines and are widely used in drug development, although they have some disadvantages, including their relative low success rate, long turn-around time, and high costs. The collagen gel droplet embedded culture drug sensitivity test (CD-DST) has been used as an in-vitro drug sensitivity test for patients with cancer because of its high success rate of primary cell culture, high sensitivity, and good clinical relevance, but it is based on an in-vitro cell culture and may not simulate the tumor microenvironment accurately. This study aims to combine a PDX model with CD-DST to evaluate the efficiency of antitumor agents. KRpep-2d, a small peptide targeting KRAS (G12D), and oxaliplatin were used to verify the feasibility of this approach. Whole-exome sequencing and Sanger sequencing were first applied to test and validate the KRAS mutation status of a panel of colorectal cancer PDX tissues. One PDX model was verified to carry KRAS (G12D) mutation and was used for in-vivo and the CD-DST drug tests. We then established the PDX mouse model from the patient with the KRAS (G12D) mutation and obtained viable cancer cells derived from the same PDX model. Next, the antitumor abilities of KRpep-2d and oxaliplatin were estimated in the PDX model and the CD-DST. We found that KRpep-2d showed no significant antitumor effect on the xenograft model or on cancer cells derived from the same PDX model. In contrast, oxaliplatin showed significant inhibitory effects in both tests. In conclusion, the PDX model in combination with the CD-DST assay is a comprehensive and feasible method of evaluating the antitumor properties of compounds and could be applied for new drug discovery.
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Affiliation(s)
- Wuguo Li
- Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Wei Chen
- Department of Pathology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, PR China
| | - Jialin Wang
- General Surgical Laboratory, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Guangyin Zhao
- Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Lianzhou Chen
- General Surgical Laboratory, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Yong Wan
- Guangzhou Darui Biotechnology Co., Ltd., Guangzhou, Guangdong, PR China
| | - Qianxin Luo
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Wenwen Li
- Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Haoji Huang
- Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Wenying Li
- Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Wu Li
- Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Yutong Yang
- Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Daici Chen
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China,Corresponding author.
| | - Qiao Su
- Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China,Corresponding author.
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