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Balhara N, Yadav R, Chauhan MB. Role of signaling pathways in endometrial cancer. Mol Biol Rep 2025; 52:408. [PMID: 40257522 DOI: 10.1007/s11033-025-10523-1] [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: 02/03/2025] [Accepted: 04/16/2025] [Indexed: 04/22/2025]
Abstract
Endometrial cancer (EC) is a prevalent gynecological malignancy with a complex molecular landscape, contributing to significant global morbidity and mortality. Dysregulated signaling pathways such as PI3K/AKT/mTOR and RAS/RAF/MEK drive EC progression by promoting uncontrolled cell proliferation, survival, angiogenesis, and metastasis. Mutations in genes like PTEN and PIK3CA further underpin tumor aggressiveness. Molecular alterations in these pathways not only serve as biomarkers for prognosis but also guide the formulation of targeted therapies, such as mTOR inhibitors and anti-angiogenic agents. While such therapies show promise, optimizing their efficacy and minimizing adverse effects requires further research. A comprehensive approach integrating early detection (e.g., addressing postmenopausal bleeding), preventive strategies (e.g., managing obesity), increasing diagnostic sensitivity (e.g., transvaginal ultrasound) and advanced molecularly tailored treatments (e.g., AI & ML) is critical to reducing the burden of this disease. By targeting key signaling pathways, leveraging AI-driven methodologies, and addressing treatment resistance, we can enhance patient outcomes, also mitigate the rising global impact of EC.
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Affiliation(s)
- Nikita Balhara
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana, 124001, India
| | - Ritu Yadav
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana, 124001, India.
| | - Meenakshi B Chauhan
- Department of Obstetrics and Gynecology, PGIMS, Rohtak, Haryana, 124001, India
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Ondič O, Michalová K, Švajdler M, Presl J, Kosťun J, Hájková V, Martínek P, Michal M. Molecular substratification of endometrial carcinomas with no special molecular profile (NSMP) by using a limited NGS custom panel may facilitate effective patient selection for the PIK3CA-targeted therapy. Virchows Arch 2025; 486:827-832. [PMID: 39235514 PMCID: PMC12018627 DOI: 10.1007/s00428-024-03905-6] [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: 06/03/2024] [Revised: 08/07/2024] [Accepted: 08/17/2024] [Indexed: 09/06/2024]
Abstract
Endometrial carcinomas (EC) of no special molecular profile (NSMP) represent the largest molecular category of EC, comprising a mixture of tumors with different histology and molecular profiles. These facts likely point to different tumor biology, clinical outcomes, and targeted therapy responses within this molecular category. The PIK3CA is currently the only targetable kinase oncoprotein directly implicated in EC carcinogenesis. Investigating a unique single-institution cohort, we attempted to stratify NSMP ECs based on the presence of the PIK3CA pathogenic mutation. Those cases were further analyzed for other well-established-associated oncogenic driver gene mutations. Histological and clinical variables were also correlated in each case. Altogether, 175 ECs were prospectively tested by a limited custom NGS panel containing ARID1A, BCOR, BRCA1, BRCA2, CTNNB1, KRAS, MLH1, MSH2, MSH6, NRAS, PIK3CA, PMS2, POLD1, POLE, PTEN,and TP53 genes. We identified 24 PIK3CA mutated cases in the group of 80 NSMP ECs, with another co-occurring mutation in at least one oncogenic driver gene (CTNNB1, PTEN, ARID1A, KRAS, BCOR, PMS2) in 19 cases. In conclusion, a limited NGS panel can effectively test EC tissue for specific pathogenetically relevant oncogene mutations. The NSMP EC category contains 30% of the PIK3CA mutated cases. Of those, 21% contain the PIK3CA mutation as a sole EC-associated oncogene mutation, while 79% harbor at least one more mutated gene. These findings may inform future healthcare planning and improve the effectiveness of EC patient selection for the PIK3CA-targeted therapy.
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Affiliation(s)
- Ondrej Ondič
- Department of Pathology, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic.
- Molecular Genetics Department, Bioptická Laboratoř s.r.o, Pilsen, Czech Republic.
| | - Květoslava Michalová
- Department of Pathology, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic
- Molecular Genetics Department, Bioptická Laboratoř s.r.o, Pilsen, Czech Republic
| | - Marián Švajdler
- Department of Pathology, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic
- Molecular Genetics Department, Bioptická Laboratoř s.r.o, Pilsen, Czech Republic
| | - Jiří Presl
- Department of Gynecology and Obstetrics, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic
| | - Jan Kosťun
- Department of Gynecology and Obstetrics, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic
| | - Veronika Hájková
- Molecular Genetics Department, Bioptická Laboratoř s.r.o, Pilsen, Czech Republic
| | - Petr Martínek
- Molecular Genetics Department, Bioptická Laboratoř s.r.o, Pilsen, Czech Republic
| | - Michal Michal
- Department of Pathology, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic
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Moufarrij S, Lakhman Y, Aghajanian C, Abu-Rustum NR, Ellenson LH, Weigelt B, Momeni-Boroujeni A. Evolutionary pathways in early-stage, non-myoinvasive endometrioid endometrial cancers of no specific molecular profile. Gynecol Oncol 2025; 192:8-14. [PMID: 39509805 DOI: 10.1016/j.ygyno.2024.10.029] [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: 07/30/2024] [Revised: 10/18/2024] [Accepted: 10/27/2024] [Indexed: 11/15/2024]
Abstract
OBJECTIVE To characterize the genomic landscape of FIGO 2009 stage IA, non-myometrial invasive endometrioid endometrial cancers (ECs) of no specific molecular profile (NSMP) and define the earliest driver genetic alterations and subsequent tumor evolution. METHODS Early-stage (FIGO 2009 stage IA), non-myoinvasive endometrioid NSMP ECs subjected to clinical tumor-normal targeted sequencing between 2014 and 2022 were identified. ECs were dichotomized into low- and high-volume disease based on gross and histologic measurement using a cutoff of 1.8 cm3. Cancer cell fractions (CCF) of somatic mutations were determined. RESULTS A total of 171 noninvasive, FIGO 2009 stage I endometrioid ECs of NSMP subtype were identified, of which the majority (n = 139; 81 %) were FIGO grade 1. The median calculated volume of disease was 1.8 cm3 at diagnosis. The ECs had on average 6 pathogenic mutations, affecting known EC cancer-related genes, including PTEN (80 %), ARID1A (52 %), PIK3CA (52 %), CTNNB1 (39 %), PIK3R1 (37 %), and KRAS (29 %). Genomic alterations did not correlate with tumor volume. PTEN mutations had the highest CCFs. Unsupervised hierarchical clustering based on CCF revealed 4 main groups characterized by: 1. clonal alterations in PTEN accompanied by PIK3CA, PIK3R1, or ARID1A alterations, 2. mutations in PIK3CA co-occurring with ARID1A alterations, 3. KRAS mutations, particularly associated with 1q high-level gain, or 4. AKT1 mutations, which uniquely occurred without concurrent PTEN, PIK3CA, or PIK3R1 alterations. CONCLUSION Stage IA non-myoinvasive NSMP ECs show genomic heterogeneity suggestive of multiple evolutionary pathways. Further studies are warranted to define whether this is a sign of early genomic drift.
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Affiliation(s)
- Sara Moufarrij
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Yulia Lakhman
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Carol Aghajanian
- Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medical College, 400 E 67th St, New York, NY 10065, USA.
| | - Nadeem R Abu-Rustum
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of OB/GYN, Weill Cornell Medical College, 400 E 67th St, New York, NY 10065, USA.
| | - Lora H Ellenson
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Britta Weigelt
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Amir Momeni-Boroujeni
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Gupta I, Gaykalova DA. Unveiling the role of PIK3R1 in cancer: A comprehensive review of regulatory signaling and therapeutic implications. Semin Cancer Biol 2024; 106-107:58-86. [PMID: 39197810 DOI: 10.1016/j.semcancer.2024.08.004] [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: 05/07/2024] [Revised: 07/11/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024]
Abstract
Phosphoinositide 3-kinase (PI3K) is responsible for phosphorylating phosphoinositides to generate secondary signaling molecules crucial for regulating various cellular processes, including cell growth, survival, and metabolism. The PI3K is a heterodimeric enzyme complex comprising of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85). The binding of the regulatory subunit, p85, with the catalytic subunit, p110, forms an integral component of the PI3K enzyme. PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) belongs to class IA of the PI3K family. PIK3R1 exhibits structural complexity due to alternative splicing, giving rise to distinct isoforms, prominently p85α and p55α. While the primary p85α isoform comprises multiple domains, including Src homology 3 (SH3) domains, a Breakpoint Cluster Region Homology (BH) domain, and Src homology 2 (SH2) domains (iSH2 and nSH2), the shorter isoform, p55α, lacks certain domains present in p85α. In this review, we will highlight the intricate regulatory mechanisms governing PI3K signaling along with the impact of PIK3R1 alterations on cellular processes. We will further delve into the clinical significance of PIK3R1 mutations in various cancer types and their implications for prognosis and treatment outcomes. Additionally, we will discuss the evolving landscape of targeted therapies aimed at modulating PI3K-associated pathways. Overall, this review will provide insights into the dynamic interplay of PIK3R1 in cancer, fostering advancements in precision medicine and the development of targeted interventions.
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Affiliation(s)
- Ishita Gupta
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Otorhinolaryngology-Head and Neck Surgery, Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA
| | - Daria A Gaykalova
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Otorhinolaryngology-Head and Neck Surgery, Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
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Yang FF, Zhao TT, Milaneh S, Zhang C, Xiang DJ, Wang WL. Small molecule targeted therapies for endometrial cancer: progress, challenges, and opportunities. RSC Med Chem 2024; 15:1828-1848. [PMID: 38911148 PMCID: PMC11187550 DOI: 10.1039/d4md00089g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 04/10/2024] [Indexed: 06/25/2024] Open
Abstract
Endometrial cancer (EC) is a common malignancy among women worldwide, and its recurrence makes it a common cause of cancer-related death. Surgery and external radiation, chemotherapy, or a combination of strategies are the cornerstone of therapy for EC patients. However, adjuvant treatment strategies face certain drawbacks, such as resistance to chemotherapeutic drugs; therefore, it is imperative to explore innovative therapeutic strategies to improve the prognosis of EC. With the development of pathology and pathophysiology, several biological targets associated with EC have been identified, including PI3K/Akt/mTOR, PARP, GSK-3β, STAT-3, and VEGF. In this review, we summarize the progress of small molecule targeted therapies in terms of both basic research and clinical trials and provide cases of small molecules combined with fluorescence properties in the clinical applications of integrated diagnosis and treatment. We hope that this review will facilitate the further understanding of the regulatory mechanism governing the dysregulation of oncogenic signaling in EC and provide insights into the possible future directions of targeted therapeutic regimens for EC treatment by developing new agents with fluorescence properties for the clinical applications of integrated diagnosis and treatment.
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Affiliation(s)
- Fei-Fei Yang
- Yixing People's Hospital Yixing Jiangsu 214200 China
| | - Tian-Tian Zhao
- School of Life Sciences and Health Engineering, Jiangnan University Wuxi 214122 China
| | - Slieman Milaneh
- School of Life Sciences and Health Engineering, Jiangnan University Wuxi 214122 China
- Department of Pharmaceutical and Chemical Industries, Higher Institute of Applied Science and Technology Damascus Syria
| | - Chun Zhang
- School of Life Sciences and Health Engineering, Jiangnan University Wuxi 214122 China
| | - Da-Jun Xiang
- Xishan People's Hospital of Wuxi City Wuxi Jiangsu 214105 China
| | - Wen-Long Wang
- Yixing People's Hospital Yixing Jiangsu 214200 China
- School of Life Sciences and Health Engineering, Jiangnan University Wuxi 214122 China
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Nie Z, Zeng K, Yan Q, Liu Y, Bian Y, Zhu J, Guo Z, He F, Shi H, Guo Y. The Relationship Between Gene Mutations and the Clinicopathological Features and Prognosis of Gastric Cancer. Int J Surg Pathol 2024; 32:486-495. [PMID: 37545327 DOI: 10.1177/10668969231188421] [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: 08/08/2023]
Abstract
Current treatments for gastric cancer (GC) are suboptimal. Potential therapeutic targets for GC were screened using next-generation sequencing. We examined many mutation genes linked to GC, including TP53 (60%), PIK3CA (19%), LRP1B (13%), and ERBB2 (12%), ARID1A (9%), KMT2C (9%), and KRAS (7%). The KMT2C, KRAS, CDK6, and ARID1A wild-type genes were dominant in diffuse-type GC (P < .05), but mutations did not influence prognosis. Patients with APC (6%) and CDH1 (8%) wild-type GC presented with vascular invasion (P < .05). Patients with ATR (2%) wild-type GC were prone to lymph node metastasis (P < .05). Patients with ARID1A (9%) wild-type GC had reduced programmed death ligand 1 expression (<1, P < .05). We found that patients who received chemotherapy had a better prognosis than those who did not (although there was no statistical difference), with platinum-based group having better prognosis and uracil combined with paclitaxel group having worse prognosis.
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Affiliation(s)
- Zunzhen Nie
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
| | - Kaixuan Zeng
- Precision Medical Research Institute, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qingguo Yan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
| | - Yuangang Liu
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
| | - Yawei Bian
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
| | - Jin Zhu
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
| | - Zhenzhen Guo
- Department III of General Surgery, Xi'an Daxing Hospital, Xi'an, China
| | - Furong He
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
| | - Hai Shi
- Department of Gastrointestinal Surgery, Xi'an Daxing Hospital, Xi'an, China
| | - Ying Guo
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
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Samudrala M, Dhaveji S, Savsani K, Dakshanamurthy S. AutoEpiCollect, a Novel Machine Learning-Based GUI Software for Vaccine Design: Application to Pan-Cancer Vaccine Design Targeting PIK3CA Neoantigens. Bioengineering (Basel) 2024; 11:322. [PMID: 38671743 PMCID: PMC11048108 DOI: 10.3390/bioengineering11040322] [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: 02/27/2024] [Revised: 03/20/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
Previous epitope-based cancer vaccines have focused on analyzing a limited number of mutated epitopes and clinical variables preliminarily to experimental trials. As a result, relatively few positive clinical outcomes have been observed in epitope-based cancer vaccines. Further efforts are required to diversify the selection of mutated epitopes tailored to cancers with different genetic signatures. To address this, we developed the first version of AutoEpiCollect, a user-friendly GUI software, capable of generating safe and immunogenic epitopes from missense mutations in any oncogene of interest. This software incorporates a novel, machine learning-driven epitope ranking method, leveraging a probabilistic logistic regression model that is trained on experimental T-cell assay data. Users can freely download AutoEpiCollectGUI with its user guide for installing and running the software on GitHub. We used AutoEpiCollect to design a pan-cancer vaccine targeting missense mutations found in the proto-oncogene PIK3CA, which encodes the p110ɑ catalytic subunit of the PI3K kinase protein. We selected PIK3CA as our gene target due to its widespread prevalence as an oncokinase across various cancer types and its lack of presence as a gene target in clinical trials. After entering 49 distinct point mutations into AutoEpiCollect, we acquired 361 MHC Class I epitope/HLA pairs and 219 MHC Class II epitope/HLA pairs. From the 49 input point mutations, we identified MHC Class I epitopes targeting 34 of these mutations and MHC Class II epitopes targeting 11 mutations. Furthermore, to assess the potential impact of our pan-cancer vaccine, we employed PCOptim and PCOptim-CD to streamline our epitope list and attain optimized vaccine population coverage. We achieved a world population coverage of 98.09% for MHC Class I data and 81.81% for MHC Class II data. We used three of our predicted immunogenic epitopes to further construct 3D models of peptide-HLA and peptide-HLA-TCR complexes to analyze the epitope binding potential and TCR interactions. Future studies could aim to validate AutoEpiCollect's vaccine design in murine models affected by PIK3CA-mutated or other mutated tumor cells located in various tissue types. AutoEpiCollect streamlines the preclinical vaccine development process, saving time for thorough testing of vaccinations in experimental trials.
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Affiliation(s)
- Madhav Samudrala
- College of Arts and Sciences, The University of Virginia, Charlottesville, VA 22903, USA
| | | | - Kush Savsani
- College of Humanities and Sciences, Virginia Commonwealth University, Richmond, VA 22043, USA
| | - Sivanesan Dakshanamurthy
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
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8
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Jia W, Luo S, Guo H, Kong D. Development of PI3Kα inhibitors for tumor therapy. J Biomol Struct Dyn 2023; 41:8587-8604. [PMID: 36221910 DOI: 10.1080/07391102.2022.2132293] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 09/28/2022] [Indexed: 10/17/2022]
Abstract
The PI3K/AKT/mTOR signaling pathway is well known to be involved in cell growth, proliferation, metabolism and other cellular physiological processes. Abnormal activation of this pathway is closely related to tumorigenesis and metastasis. As the starting node of the pathway, PI3K is known to contain 4 isoforms, including PI3Kα, a heterodimer composed of the catalytic subunit p110α and the regulatory subunit p85. PIK3CA, which encodes p110α, is frequently mutated in cancer, especially breast cancer. Abnormal activation of PI3Kα promotes cancer cell proliferation, migration, invasion, and angiogenesis; therefore, PI3Kα has become a key target for the development of anticancer drugs. The hinge region and the region of the mutation site in the PI3Kα protein are important for designing PI3Kα-specific inhibitors. As the group shared by the most PI3Kα-specific inhibitors reported thus far, carboxamide can produce hydrogen bonds with Gln859 and Ser854. Gln859 is specific to the p110α protein in producing hydrogen bond interactions with PI3Kα-specific inhibitors and this is a key point for designing PI3Kα inhibitors. To date, alpelisib is the only PI3Kα inhibitor approved for the treatment of breast cancer. Several other PI3Kα inhibitors are under evaluation in clinical trials. In this review, we briefly describe PI3Kα and its role in tumorigenesis, summarize the clinical trial results of some PI3Kα inhibitors as well as the synthetic routes of alpelisib, and finally give our proposal for the development of novel PI3Kα inhibitors for tumor therapy. HighlightsWe summarize the progress of PI3Kα and PI3Kα inhibitors in cancer from the second half of the 20th century to the present.We describe the clinical trial results of PI3Kα inhibitors as well as the synthetic routes of the only approved PI3Kα inhibitor alpelisib.Crystal structure of alpelisib bound to the PI3Kα receptor binding domain.This review gives proposal for the development of novel PI3Kα inhibitors and will serve as a complementary summary to other reviews in the research field of PI3K inhibitors.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Wenqing Jia
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Shuyu Luo
- School of Stomatology, Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Han Guo
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
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9
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Chang L, Jung NY, Atari A, Rodriguez DJ, Kesar D, Song TY, Rees MG, Ronan M, Li R, Ruiz P, Chaturantabut S, Ito T, van Tienen LM, Tseng YY, Roth JA, Sellers WR. Systematic profiling of conditional pathway activation identifies context-dependent synthetic lethalities. Nat Genet 2023; 55:1709-1720. [PMID: 37749246 DOI: 10.1038/s41588-023-01515-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 08/22/2023] [Indexed: 09/27/2023]
Abstract
The paradigm of cancer-targeted therapies has focused largely on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been deeply characterized. In this study, we sought to systematically identify context-specific gene-activation-induced lethalities in cancer. To this end, we developed a method for gain-of-function genetic perturbations simultaneously across ~500 barcoded cancer cell lines. Using this approach, we queried the pan-cancer vulnerability landscape upon activating ten key pathway nodes, revealing selective activation dependencies of MAPK and PI3K pathways associated with specific biomarkers. Notably, we discovered new pathway hyperactivation dependencies in subsets of APC-mutant colorectal cancers where further activation of the WNT pathway by APC knockdown or direct β-catenin overexpression led to robust antitumor effects in xenograft and patient-derived organoid models. Together, this study reveals a new class of conditional gene-activation dependencies in cancer.
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Affiliation(s)
- Liang Chang
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Nancy Y Jung
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Adel Atari
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | - Devishi Kesar
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Tian-Yu Song
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | | | - Melissa Ronan
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Ruitong Li
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Paloma Ruiz
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Saireudee Chaturantabut
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Biopharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand
| | - Takahiro Ito
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Laurens M van Tienen
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Yuen-Yi Tseng
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | - William R Sellers
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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10
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Chessa TAM, Jung P, Anwar A, Suire S, Anderson KE, Barneda D, Kielkowska A, Sadiq BA, Lai IW, Felisbino S, Turnham DJ, Pearson HB, Phillips WA, Sasaki J, Sasaki T, Oxley D, Spensberger D, Segonds-Pichon A, Wilson M, Walker S, Okkenhaug H, Cosulich S, Hawkins PT, Stephens LR. PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate. Mol Cell 2023; 83:2991-3009.e13. [PMID: 37567175 DOI: 10.1016/j.molcel.2023.07.015] [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: 09/22/2022] [Revised: 05/05/2023] [Accepted: 07/13/2023] [Indexed: 08/13/2023]
Abstract
The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2 phosphatase, PTEN. Despite huge research investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signaling and constrained by pathway feedback. In the absence of PTEN, the network is dramatically remodeled. A poorly understood YXXM- and PIP3/PI(3,4)P2-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT phosphorylation, and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and Src-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y419 phosphorylation of hSrc correlated with PI3K pathway activity in human prostate cancers. We propose that in PTEN-null cells receptor-independent, Src-dependent tyrosine phosphorylation of PLEKHS1 creates positive feedback that escapes homeostasis, drives PIP3 signaling, and supports tumor progression.
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Affiliation(s)
| | - Piotr Jung
- Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK
| | - Arqum Anwar
- Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK
| | - Sabine Suire
- Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK
| | - Karen E Anderson
- Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK
| | - David Barneda
- Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK
| | - Anna Kielkowska
- Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK
| | - Barzan A Sadiq
- Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK
| | - Ieng Wai Lai
- Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK
| | - Sergio Felisbino
- Department of Structural and Functional Biology, São Paulo State University, Botucatu, SP CEP: 18618-689, Brazil
| | - Daniel J Turnham
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff CF24 4HQ, UK
| | - Helen B Pearson
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff CF24 4HQ, UK
| | - Wayne A Phillips
- Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
| | - Junko Sasaki
- Department of Biochemical Pathophysiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Takehiko Sasaki
- Department of Biochemical Pathophysiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - David Oxley
- Mass Spectrometry Facility, Babraham Institute, Cambridge CB22 3AT, UK
| | | | | | - Michael Wilson
- Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK
| | - Simon Walker
- Imaging Facility, Babraham Institute, Cambridge CB22 3AT, UK
| | | | | | | | - Len R Stephens
- Signalling Programme, Babraham Institute, Cambridge CB22 3AT, UK.
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11
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Chukkalore D, Rajavel A, Asti D, Dhar M. Genomic determinants in advanced endometrial cancer patients with sustained response to hormonal therapy- case series and review of literature. Front Oncol 2023; 13:1188028. [PMID: 37465112 PMCID: PMC10351014 DOI: 10.3389/fonc.2023.1188028] [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: 03/16/2023] [Accepted: 06/19/2023] [Indexed: 07/20/2023] Open
Abstract
The incidence of endometrial cancer is increasing, however treatment options for advanced disease are limited. Hormonal therapy has demonstrated positive outcomes for Stage IV EC. Next generation sequencing (NGS) has increased our understanding of molecular mechanisms driving EC. In this case series, we selected six patients at our institution with Stage IV, hormone receptor positive, endometrial cancer currently being treated with hormonal therapy. All patients achieved SD for at least ≥ 1.5 years. We studied NGS data on all six patients to assess for any common genomic marker which could predict the SD of at least 1.5 years achieved in this group. Institutional Review Board (IRB) approval was obtained from Staten Island University Hospital and Northwell Health, New York. PTEN, PIK3CA, PIK3R1, and ARID1A mutations were found in 83%, 67% 50%, and 67% of patients respectively. TP53 and FGFR2 were both found in 50% of patients. All patients were positive for estrogen and/or progesterone receptor (ER+ and/or PR+). We did not find any one common mutation that could have predicted the observed response (or SD of ≥1.5 years) to hormone therapy. However, our data reflects the prevalence of various mutations reported in literature: (1) Hormone Receptor status is a positive prognostic indicator (2) PTEN/PIK3CA mutations can occur concurrently in EC (3) ARID1A coexists with PTEN (4) FGFR and PTEN pathways may be interlinked. We suggest NGS be employed frequently in patients with endometrial cancer to identify targetable mutations. Additional larger studies are needed to characterize the interplay between mutations.
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12
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Oropeza-de Lara SA, Garza-Veloz I, Berthaud-González B, Martinez-Fierro ML. Circulating and Endometrial Tissue microRNA Markers Associated with Endometrial Cancer Diagnosis, Prognosis, and Response to Treatment. Cancers (Basel) 2023; 15:2686. [PMID: 37345024 DOI: 10.3390/cancers15102686] [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: 03/18/2023] [Revised: 04/28/2023] [Accepted: 05/08/2023] [Indexed: 06/23/2023] Open
Abstract
In developed countries, endometrial cancer (EC) is one of the most common neoplasms of the female reproductive system. MicroRNAs (miRs) are a class of single-stranded noncoding RNA molecules with lengths of 19-25 nucleotides that bind to target messenger RNA (mRNA) to regulate post-transcriptional gene expression. Although there is a large amount of research focused on identifying miRs with a diagnostic, prognostic, or response to treatment capacity in EC, these studies differ in terms of experimental methodology, types of samples used, selection criteria, and results obtained. Hence, there is a large amount of heterogeneous information that makes it difficult to identify potential miR biomarkers. We aimed to summarize the current knowledge on miRs that have been shown to be the most suitable potential markers for EC. We searched PubMed and Google Scholar without date restrictions or filters. We described 138 miRs with potential diagnostic, prognostic, or treatment response potential in EC. Seven diagnostic panels showed higher sensitivity and specificity for the diagnosis of EC than individual miRs. We further identified miRs up- or downregulated depending on the FIGO stage, precursor lesions, and staging after surgery, which provides insight into which miRs are expressed chronologically depending on the disease stage and/or that are modulated depending on the tumor grade based on histopathological evaluation.
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Affiliation(s)
- Sergio Antonio Oropeza-de Lara
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, Carretera Zacatecas-Guadalajara Km 6, Ejido La Escondida, Zacatecas 98160, Mexico
| | - Idalia Garza-Veloz
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, Carretera Zacatecas-Guadalajara Km 6, Ejido La Escondida, Zacatecas 98160, Mexico
| | - Bertha Berthaud-González
- Hospital General Zacatecas "Luz González Cosío", Servicios de Salud de Zacatecas, Zacatecas 98160, Mexico
| | - Margarita L Martinez-Fierro
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, Carretera Zacatecas-Guadalajara Km 6, Ejido La Escondida, Zacatecas 98160, Mexico
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13
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Alves LB, Moura AC, Amorim Dos Santos J, Borges GA, Guerra ENS. Pharmacological PI3K inhibition in head and neck squamous cell carcinoma: A systematic review. Toxicol In Vitro 2023; 88:105558. [PMID: 36681288 DOI: 10.1016/j.tiv.2023.105558] [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: 05/11/2022] [Revised: 12/12/2022] [Accepted: 01/15/2023] [Indexed: 01/20/2023]
Abstract
BACKGROUND This systematic review aimed to investigate the in vitro and in vivo effects of phosphatidylinositol-3-kinase (PI3K) inhibitors on head and neck squamous cell carcinoma (HNSCC). Considering the role of PI3K and its downstream effectors in cell proliferation, invasion, and survival, it is reasonable to expect that treatment with PI3K inhibitors could control HNSCC onset and progression. Thus, the research question for our review was whether pharmacological inhibition of PI3K affects HNSCC progression. METHODS In vitro and in vivo studies were selected from six databases. We collected data regarding cell viability, apoptosis, and the regulation of protein expression levels from in vitro studies. For the in vivo studies, we analyzed the reduction in tumor size or gene and protein expression. RESULTS The included studies showed reduced cell proliferation and apoptosis after treatment with PI3K inhibitors. PI3K inhibitors in combination with other drugs had an enhanced anticancer effects compared to those of single-drug treatments. CONCLUSIONS The results support the potential of PI3K inhibitors as candidates for clinical trials in HNSCC.
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Affiliation(s)
- L B Alves
- Laboratory of Oral Histopathology, School of Health Sciences, University of Brasília, Brasília, Brazil
| | - A C Moura
- Laboratory of Oral Histopathology, School of Health Sciences, University of Brasília, Brasília, Brazil
| | - J Amorim Dos Santos
- Laboratory of Oral Histopathology, School of Health Sciences, University of Brasília, Brasília, Brazil
| | - G A Borges
- Department of Oral Medicine and Periodontics, Faculty of Dentistry, University of Michigan, Ann Arbor, United States
| | - E N S Guerra
- Laboratory of Oral Histopathology, School of Health Sciences, University of Brasília, Brasília, Brazil.
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14
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Bredin HK, Krakstad C, Hoivik EA. PIK3CA mutations and their impact on survival outcomes of patients with endometrial cancer: A systematic review and meta-analysis. PLoS One 2023; 18:e0283203. [PMID: 36943861 PMCID: PMC10030019 DOI: 10.1371/journal.pone.0283203] [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: 10/20/2022] [Accepted: 03/03/2023] [Indexed: 03/23/2023] Open
Abstract
Several studies have highlighted the frequent alterations of the PI3K pathway in endometrial cancer leading to increased signaling activation with potential for targeted treatment. The objective of this meta-study was to evaluate how PIK3CA exon 9/20 mutations affect survival in endometrial cancer patients, based on available literature. Topic-based search strategies were applied to databases including CENTRAL, MEDLINE, Embase, Web of Science and COSMIC. All studies assessing the impact of mutations in exon 9 and exon 20 of PIK3CA on survival rates of endometrial cancer patients were selected for inclusion. Statistical meta-analysis was performed with the 'meta' package in RStudio. Overall, 7 of 612 screened articles were included in the present study, comprising 1098 women with endometrial cancer. Meta-analysis revealed a tendency of impaired survival for patients with PIK3CA exon 9 and/or exon 20 mutations (RR 1.28; 95% CI 0.84, 1.94; p = 0.25). This tendency was consistent in subgroup analyses stratified by histologic type or -grade, with the most prominent effect in low-grade endometrial cancers (RR 2.04; 95% CI 0.90, 4.62; p = 0.09). In summary, these results suggest that PIK3CA mutations negatively influence survival outcomes of patients with endometrial cancer, including those with low-grade tumors.
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Affiliation(s)
- Hanna K. Bredin
- Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
| | - Camilla Krakstad
- Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
| | - Erling A. Hoivik
- Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
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15
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Banet N, Masnick M, Quddus MR. Evaluation of Saccharomyces cerevisiae -like 1 (SEC14L1) in Gynecologic Malignancies Shows Overexpression in Endometrial Serous Carcinoma. Int J Gynecol Pathol 2023; 42:136-142. [PMID: 35283446 DOI: 10.1097/pgp.0000000000000866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Saccharomyces cerevisiae -like 1 ( SEC14L1 ) is a member of the SEC14 family and is involved in liposoluble vitamin transfer, and in a large cohort of breast cancer cases, was one of the genes most significantly associated with lymphovascular invasion (LVI), and had a significant relationship with human epidermal growth factor receptor 2 status, survival, and histologic grade. In this study, 111 separate gynecologic tumors were studied for SEC14L1 protein expression, including: uterine adenosarcoma, ovarian clear cell carcinoma, endometrial stromal sarcoma, endometrioid carcinoma of the uterus, high-grade serous carcinoma, ovarian endometrioid carcinoma, uterine leiomyosarcoma, low-grade serous carcinoma, uterine carcinosarcoma, and uterine serous carcinoma (USC). Overall, LVI was noted in 31/111 (28%) cases, highest in uterine carcinosarcoma (5/11; 45%), high-grade serous carcinoma (9/21; 43%), and ovarian clear cell carcinoma (4/10; 40%). SEC14L1 was positive in 25/111 (23%) cases; the highest percentage and only statistically significant finding by tumor type was USC at 9/12 (75%) cases positive. No relation between LVI or survival and SEC14L1 expression was noted. The relation between USC, a tumor known to show human epidermal growth factor receptor 2 overexpression and SEC14L1 is a novel finding, the significance of which warrants further study.
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16
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Li Y, Zhu C, Xie H, Chen Y, Lv W, Xie X, Wang X. Molecular profile-based recommendations for postoperative adjuvant therapy in early endometrial cancer with high-intermediate or intermediate risk: a Chinese randomized phase III trial (PROBEAT). J Gynecol Oncol 2023; 34:e37. [PMID: 36659832 PMCID: PMC9995864 DOI: 10.3802/jgo.2023.34.e37] [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: 06/06/2022] [Revised: 10/17/2022] [Accepted: 12/28/2022] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND The use of molecular categorisation is shifting paradigm towards the use of molecular information to refine risk stratification in endometrial cancer (EC). To date, evidence to support molecular-guided therapies is limited to retrospective studies and secondary molecular analyses of patients receiving standard treatment. The PROBEAT study is the first randomized phase III trial to evaluate tailored adjuvant treatment based on WHO-endorsed molecular classification in Chinese EC patients. It is expected to provide a clinical decision-making tool for adjuvant treatment of patients with high-intermediate risk (HIR) or intermediate risk (IR) EC to better optimise and personalise patient care and increase relapse-free survival. METHODS The PROBEAT trial is a prospective, multicentre study led by Women's Hospital of Zhejiang University Gynaecologic Oncology Group. Recruitment started on January 24, 2022, and 590 patients with HIR or IR endometrioid EC are expected to be recruited from 13 clinical centres in China. All tumor tissues will be classified into four molecular subtypes (POLEmut, MMRd, p53abn, or NSMP) based on WHO-endorsed molecular classification. Patients will be randomly assigned at a 2:1 ratio to either experimental arm and will receive molecular profile-based adjuvant treatment (observation in the POLEmut subgroup, vaginal brachytherapy in the MMRd or NSMP subgroup, or chemoradiotherapy in the p53abn subgroup) or to standard arm and will receive preferred adjuvant radiotherapy as recommended by the recent National Comprehensive Cancer Network guidelines version 1 (2022). The primary outcome is 3-year rates of recurrence. Secondary outcomes are relapse-free survival, overall survival, adverse events and health-related cancer-specific quality of life. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05179447.
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Affiliation(s)
- Yang Li
- Department of Gynecology and Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Changkun Zhu
- Department of Gynecology and Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Hongyu Xie
- Department of Clinical Research Center, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yaxia Chen
- Department of Gynecology and Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Weiguo Lv
- Department of Gynecology and Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xing Xie
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xinyu Wang
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
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17
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Cheng G, An F, Cao Z, Zheng M, Zhao Z, Wu H. DPY30 promotes the growth and survival of osteosarcoma cell by regulating the PI3K/AKT signal pathway. Eur J Histochem 2022; 67:3413. [PMID: 36546421 PMCID: PMC9827427 DOI: 10.4081/ejh.2023.3413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 09/11/2022] [Indexed: 12/24/2022] Open
Abstract
Osteosarcoma (OS) is characterized by aggressive features including invasiveness and high incidence of metastasis. OS patients with metastases are difficult to treat and suffer from a poor prognosis. DPY30 (protein dpy-30 homolog) is a key component of SET1/MLL family of H3K4 methyltransferases, which is implicated in the progression of multiple cancers. However, the potential functional engagement of DPY30 in OS remains to be unveiled. The objective of this study is to investigate the potential roles of DPY30 in the regulation of malignant phenotypes of OS cells. We examined DPY30 expression from a published dataset (GSE28424) as well as in OS tissues and adjacent normal tissues from OS patients. The association of DPY30 expression level and clinicopathologic parameters was assessed by Chi-square test. The role of DPY30 in regulating the malignant phenotype of OS cells and tumorigenesis was examined by in vitro functional assays and xenograft mouse model. We reported an upregulation of DPY30 in OS tumor tissues in both published dataset and clinical samples. A high level of DPY30 expression was associated with larger tumor size and more metastasis in OS patients, as well as poor overall survival. DPY30 knockdown in OS cells significantly impairs proliferation, migration and invasion, but induced cellular apoptosis. We further demonstrated that the agonist of PI3K/AKT pathway can rescue the inhibitory effects of DPY30 knockdown in OS cells. Together, our data indicate that DPY30 functions as an oncogene to promote the malignancy of OS cells possibly through PI3K/AKT pathway. The dependency of OS cells on DPY30 overexpression is a targetable vulnerability in OS cells.
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Affiliation(s)
- Gong Cheng
- Department of Orthopedics, Yantaishan Hospital, Yantai City, Shandong Province,*Gong Cheng and Fengmin An are co-first authors
| | - Fengmin An
- Department of Sports Medicine, Yantai Affiliated Hospital of Binzhou Medical University, Yantai City, Shandong Province, China,*Gong Cheng and Fengmin An are co-first authors
| | - Zhilin Cao
- Department of Orthopedics, Yantaishan Hospital, Yantai City, Shandong Province
| | - Mingdi Zheng
- Department of Orthopedics, Yantaishan Hospital, Yantai City, Shandong Province
| | - Zhongyuan Zhao
- Department of Orthopedics, Yantaishan Hospital, Yantai City, Shandong Province
| | - Hao Wu
- Department of Orthopedics, Yantaishan Hospital, Yantai City, Shandong Province,Correspondence: Hao Wu, Department of Orthopedics, Yantaishan Hospital, No. 10087 Science and Technology Avenue, Laishan District, Yantai City 246003, Shandong Province, China. Tel. +86.0535.6863159.
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18
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Deng S, Leong HC, Datta A, Gopal V, Kumar AP, Yap CT. PI3K/AKT Signaling Tips the Balance of Cytoskeletal Forces for Cancer Progression. Cancers (Basel) 2022; 14:1652. [PMID: 35406424 PMCID: PMC8997157 DOI: 10.3390/cancers14071652] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/13/2022] [Accepted: 03/21/2022] [Indexed: 02/01/2023] Open
Abstract
The PI3K/AKT signaling pathway plays essential roles in multiple cellular processes, which include cell growth, survival, metabolism, and motility. In response to internal and external stimuli, the PI3K/AKT signaling pathway co-opts other signaling pathways, cellular components, and cytoskeletal proteins to reshape individual cells. The cytoskeletal network comprises three main components, which are namely the microfilaments, microtubules, and intermediate filaments. Collectively, they are essential for many fundamental structures and cellular processes. In cancer, aberrant activation of the PI3K/AKT signaling cascade and alteration of cytoskeletal structures have been observed to be highly prevalent, and eventually contribute to many cancer hallmarks. Due to their critical roles in tumor progression, pharmacological agents targeting PI3K/AKT, along with cytoskeletal components, have been developed for better intervention strategies against cancer. In our review, we first discuss existing evidence in-depth and then build on recent advances to propose new directions for therapeutic intervention.
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Affiliation(s)
- Shuo Deng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (S.D.); (V.G.)
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
| | - Hin Chong Leong
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore;
- Departments of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Arpita Datta
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore;
| | - Vennila Gopal
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (S.D.); (V.G.)
| | - Alan Prem Kumar
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore;
- Departments of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- National University Cancer Institute, National University Health System, Singapore 119074, Singapore
| | - Celestial T. Yap
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (S.D.); (V.G.)
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
- National University Cancer Institute, National University Health System, Singapore 119074, Singapore
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19
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Singla RK, Behzad S, Khan J, Tsagkaris C, Gautam RK, Goyal R, Chopra H, Shen B. Natural Kinase Inhibitors for the Treatment and Management of Endometrial/Uterine Cancer: Preclinical to Clinical Studies. Front Pharmacol 2022; 13:801733. [PMID: 35264951 PMCID: PMC8899191 DOI: 10.3389/fphar.2022.801733] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/17/2022] [Indexed: 02/05/2023] Open
Abstract
Endometrial cancer (EC) is the sixth most prevalent type of cancer among women. Kinases, enzymes mediating the transfer of adenosine triphosphate (ATP) in several signaling pathways, play a significant role in carcinogenesis and cancer cells’ survival and proliferation. Cyclin-dependent kinases (CDKs) are involved in EC pathogenesis; therefore, CDK inhibitors (CDKin) have a noteworthy therapeutic potential in this type of cancer, particularly in EC type 1. Natural compounds have been used for decades in the treatment of cancer serving as a source of anticancer bioactive molecules. Many phenolic and non-phenolic natural compounds covering flavonoids, stilbenoids, coumarins, biphenyl compounds, alkaloids, glycosides, terpenes, and terpenoids have shown moderate to high effectiveness against CDKin-mediated carcinogenic signaling pathways (PI3K, ERK1/2, Akt, ATM, mTOR, TP53). Pharmaceutical regimens based on two natural compounds, trabectedin and ixabepilone, have been investigated in humans showing short and midterm efficacy as second-line treatments in phase II clinical trials. The purpose of this review is twofold: the authors first provide an overview of the involvement of kinases and kinase inhibitors in the pathogenesis and treatment of EC and then discuss the existing evidence about natural products’ derived kinase inhibitors in the management of the disease and outline relevant future research.
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Affiliation(s)
- Rajeev K Singla
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.,IGlobal Research and Publishing Foundation, New Delhi, India
| | - Sahar Behzad
- Evidence-based Phytotherapy and Complementary Medicine Research Center, Alborz University of Medical Sciences, Karaj, Iran.,Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Johra Khan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, Saudi Arabia.,Health and Basic Sciences Research Center, Majmaah University, Majmaah, Saudi Arabia
| | | | - Rupesh K Gautam
- Department of Pharmacology, MM School of Pharmacy, MM University, Ambala, India
| | - Rajat Goyal
- Department of Pharmacology, MM School of Pharmacy, MM University, Ambala, India
| | | | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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20
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Tanos P, Dimitriou S, Gullo G, Tanos V. Biomolecular and Genetic Prognostic Factors That Can Facilitate Fertility-Sparing Treatment (FST) Decision Making in Early Stage Endometrial Cancer (ES-EC): A Systematic Review. Int J Mol Sci 2022; 23:2653. [PMID: 35269800 PMCID: PMC8910305 DOI: 10.3390/ijms23052653] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/12/2022] [Accepted: 02/22/2022] [Indexed: 02/01/2023] Open
Abstract
Endometrial cancer occurs in up to 29% of women before 40 years of age. Seventy percent of these patients are nulliparous at the time. Decision making regarding fertility preservation in early stage endometrial cancer (ES-EC) is, therefore, a big challenge since the decision between the risk of cancer progression and a chance to parenthood needs to be made. Sixty-two percent of women with complete remission of ES-EC after fertility-sparing treatment (FST) report to have a pregnancy wish which, if not for FST, they would not be able to fulfil. The aim of this review was to identify and summarise the currently established biomolecular and genetic prognostic factors that can facilitate decision making for FST in ES-EC. A comprehensive search strategy was carried out across four databases; Cochrane, Embase, MEDLINE, and PubMed; they were searched between March 1946 and 22nd December 2022. Thirty-four studies were included in this study which was conducted in line with the PRISMA criteria checklist. The final 34 articles encompassed 9165 patients. The studies were assessed using the Critical Appraisal Skills Program (CASP). PTEN and POLE alterations we found to be good prognostic factors of ES-EC, favouring FST. MSI, CTNNB1, and K-RAS alterations were found to be fair prognostic factors of ES-EC, favouring FST but carrying a risk of recurrence. PIK3CA, HER2, ARID1A, P53, L1CAM, and FGFR2 were found to be poor prognostic factors of ES-EC and therefore do not favour FST. Clinical trials with bigger cohorts are needed to further validate the fair genetic prognostic factors. Using the aforementioned good and poor genetic prognostic factors, we can make more confident decisions on FST in ES-EC.
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Affiliation(s)
- Panayiotis Tanos
- Institute of Applied Health Sciences, University of Aberdeen & Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK
| | - Savvas Dimitriou
- Aberdeen Fertility Centre, NHS Grampian and University of Aberdeen, Aberdeen AB25 2ZN, UK;
| | - Giuseppe Gullo
- In Vitro Fertilization Unit (IVF Unit), Azienda Ospedaliera Ospedali Riuniti, Villa Sofia Cervello, 90146 Palermo, Italy;
| | - Vasilios Tanos
- Department of Obstetrics and Gynecology, Aretaeio Hospital, Nicosia 2024, Cyprus;
- St. Georges’ Medical School, University of Nicosia, Nicosia 2408, Cyprus
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21
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Choi J, Holowatyj AN, Du M, Chen Z, Wen W, Schultz N, Lipworth L, Guo X. Distinct Genomic Landscapes in Early-Onset and Late-Onset Endometrial Cancer. JCO Precis Oncol 2022; 6:e2100401. [PMID: 35108035 PMCID: PMC8820918 DOI: 10.1200/po.21.00401] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/26/2021] [Accepted: 12/22/2021] [Indexed: 02/04/2023] Open
Abstract
PURPOSE The spectrum of somatic mutations among women with endometrial cancer (EC) younger than 50 years (early-onset EC) remains unknown. We investigated distinct somatic mutation patterns among early-onset and late-onset (age ≥ 50 years) EC patients. METHODS This cohort study included individuals age 18+ years diagnosed with pathologically confirmed EC in the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE, v9.1) consortium. We explored tumor mutational burden (TMB) and genomic patterns of EC by age at clinical sequencing using multivariable regression models adjusted for race, ethnicity, histology, sequencing assay, sample type, and TMB. RESULTS Among 2,425 women with EC, 176 (7.3%) had early-onset EC and 1,923 (79.3%) had nonhypermutated (< 17.78 mutations/Mb) tumors. TMB significantly differed across age and histology groups. Among nonhypermutated ECs, early-onset patients had significantly lower odds of presenting with nonsilent FGFR2 and PIK3R1 somatic mutations compared with late-onset EC patients in adjusted models (FGFR2: odds ratio [OR] = 0.18, 95% CI, 0.04 to 0.76; PIK3R1: OR = 0.54, 95% CI, 0.31 to 0.92). By contrast, early-onset EC patients had increased odds of presenting with nonsilent CTNNB1 and BRCA2 mutations compared with late-onset patients (CTNNB1: OR = 3.32, 95% CI, 2.14 to 5.16; BRCA2: OR = 4.01, 95% CI, 1.55 to 10.38). Subsequent analyses stratified by race, ethnicity, and tumor histology identified distinct patterns of APC, KMT2D, KMT2C, and KRAS by race, ethnicity, and PTEN and APC patterns by histologic subtypes. CONCLUSION Early-onset EC harbors a unique genomic landscape compared with late-onset disease. A distinct molecular phenotype of early-onset EC provides novel insights into a unique etiology and may yield clinical implications for developing targeted treatment modalities for younger patients.
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Affiliation(s)
- Jungyoon Choi
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Andreana N. Holowatyj
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Mengmeng Du
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Zhishan Chen
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Wanqing Wen
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Nikolaus Schultz
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Loren Lipworth
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Xingyi Guo
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN
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22
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Brito C, Tomás A, Azevedo A, Esteves S, Mafra M, Roque L, Pojo M. PIK3CA Mutations in Diffuse Gliomas: An Update on Molecular Stratification, Prognosis, Recurrence, and Aggressiveness. CLINICAL MEDICINE INSIGHTS: ONCOLOGY 2022; 16:11795549211068804. [PMID: 35023985 PMCID: PMC8743979 DOI: 10.1177/11795549211068804] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/06/2021] [Indexed: 11/15/2022] Open
Abstract
Introduction: PIK3CA is one of the most mutated oncogenes in solid tumors. In breast cancer (ER-positive, HER2-negative), these events represent a predictive biomarker of response to alpelisib. In glioblastomas (GBM), PIK3CA mutations were described as early constitutive events. Here, we investigated PIK3CA mutational profile across glioma molecular subgroups and its relevance during glioma recurrence. Furthermore, PIK3CA mutations’ effect in PI3K pathway, prognosis, and response to therapy was also explored. Material and Methods: Exons 10 and 21 of PIK3CA mutations were evaluated in 394 gliomas and 19 glioma recurrences from Instituto Português de Oncologia Lisboa Francisco Gentil (IPOLFG) and compared with The Cancer Genome Atlas (TCGA) data. TIMER2.0 and NetMHCpan4.1 were used to assess the immune-microenvironment contribution. Results: PIK3CA mutations were identified among all glioma subgroups, although with no impact on their stratification or prognosis. In both cohorts (IPOLFG and TCGA), PIK3CA mutation frequencies in IDH-mutant and IDH-wild-type GBM were similar (IPOLFG: 9% and 3%; TCGA: 8% and 2%). These mutations were not mutually exclusive with PTEN deletion and EGFR amplification. Despite their reduced frequency, we discovered PIK3CA mutations were maintained during glioma recurrence regardless of administered therapies. The immune microenvironment might not contribute to this phenotype as PIK3CA mutations did not influence immune cell infiltration. Conclusions: Despite the absence of a predominant effect in glioma stratification, PIK3CA mutations were maintained during glioma recurrence, possibly contributing to glioma cell survival, representing promising therapeutic targets in recurrent glioma. Nevertheless, understanding the potential synergistic effects between PIK3CA mutations, PTEN deletion, and EGFR amplification is pivotal to targeted therapies’ efficiency.
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Affiliation(s)
- Cheila Brito
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal
| | - Ana Tomás
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal
| | - Ana Azevedo
- Serviço de Neurologia, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal
- Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
| | - Susana Esteves
- Unidade de Investigação Clínica (UIC), Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal
| | - Manuela Mafra
- Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal
| | - Lúcia Roque
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal
| | - Marta Pojo
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal
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Wang Q, Wang J, Wang J, Ju X, Zhang H. Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment. Toxicol Res (Camb) 2021; 10:1077-1084. [PMID: 34956612 PMCID: PMC8692723 DOI: 10.1093/toxres/tfab107] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/13/2021] [Accepted: 10/27/2021] [Indexed: 12/20/2022] Open
Abstract
Shikonin is one of the major bioactive components of Lithospermum erythrorhizon. It has a good killing effect in a variety of tumor cells. Its antitumor effect involves multiple targets and pathways and has received extensive attention and study in recent years. In this review, we systematically review recent progress in determining the antitumor mechanism of shikonin and its derivatives, specifically their induction of reactive oxygen species production, inhibition of EGFR and PI3K/AKT signaling pathway activation, inhibition of angiogenesis and induction of apoptosis and necroptosis. We also discuss the application of nanoparticles loaded with shikonin in the targeted therapy of various cancers. Finally, we suggest new strategies for the clinical application of shikonin and its derivatives.
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Affiliation(s)
- Qiang Wang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, PR China
| | - Jing Wang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, PR China
| | - Jiayou Wang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, PR China
| | - Xiaoli Ju
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Heng Zhang
- Department of General Surgery, Nanjing Lishui District People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
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24
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Zhang X, Niu Y, Huang Y. Melatonin inhibits cell proliferation in a rat model of breast hyperplasia by mediating the PTEN/AKT pathway. Oncol Rep 2021; 45:66. [PMID: 34184749 PMCID: PMC8020212 DOI: 10.3892/or.2021.8017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 02/19/2021] [Indexed: 11/09/2022] Open
Abstract
In the present study, a rat model of breast hyperplasia was established via the administration of estradiol benzoate and progesterone. Subsequent changes associated with breast hyperplasia were then investigated by measuring the diameter and height of the nipples and by staining breast tissue with hematoxylin and eosin. The proliferation and apoptosis of hyperplastic cells in the breast tissue were then determined by analyzing the expression of proliferating cell nuclear antigen (PCNA) and cleaved-caspase-3 by immunohistochemistry and TUNEL staining. We also determined the expression of proteins associated with the phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) signaling pathway by western blotting. Melatonin treatment led to a significant reduction in the degree of breast hyperplasia (P<0.05), a significant reduction in PCNA, a significant increase in the level of apoptosis (P<0.05), a significant increase in PTEN (P<0.05), and a significant reduction in AKT/p-AKT (P<0.05). Furthermore, melatonin significantly decreased the aggravation of breast hyperplasia induced by application of a PTEN inhibitor. Melatonin reduced the degree of breast hyperplasia, reduced the proliferation of hyperplastic breast tissue cells, and promoted cell apoptosis in hyperplastic tissue. These effects were achieved by the specific regulation of proteins in the PTEN/PI3K/AKT axis.
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Affiliation(s)
- Xiangjian Zhang
- Department of Surgical Oncology, Wenzhou Central Hospital, Wenzhou, Zhejiang 325000, P.R. China
| | - Yingqun Niu
- Department of Surgical Oncology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Yibo Huang
- Department of Surgical Oncology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
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25
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Shen K, Yang L, Li FY, Zhang F, Ding LL, Yang J, Lu J, Wang NN, Wang Y. Research progress of PARP inhibitor monotherapy and combination therapy for endometrial cancer. Curr Drug Targets 2021; 23:145-155. [PMID: 34139979 DOI: 10.2174/1389450122666210617111304] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/14/2021] [Accepted: 05/26/2021] [Indexed: 12/24/2022]
Abstract
Endometrial cancer is one of the three most common malignant tumors in the female reproductive system. Advanced and recurrent endometrial cancers have poor prognoses and lack effective treatments. Poly(ADP-ribose) polymerase (PARP) inhibitors have been applied to many different types of tumors, and they can selectively kill tumor cells that are defective in homologous recombination repair. Endometrial cancer is characterized by mutations in homologous recombination repair genes; accordingly, PARP inhibitors have achieved positive results in off-label treatments of endometrial cancer cases. Clinical trials of PARP inhibitors as monotherapies and within combination therapies for endometrial cancer are ongoing. For this review, we searched PubMed with "endometrial cancer" and "PARP inhibitor" as keywords, and we used "olaparib", "rucaparib", "niraparib" and "talazoparib" as search terms in clinicaltrials.gov for ongoing trials. The literature search ended in October 2020, and only English-language publications were selected. Multiple studies confirm that PARP inhibitors play an important role in killing tumor cells with defects in homologous recombination repair. Its combination with immune checkpoint inhibitors, PI3K/AKT/mTOR pathway inhibitors, cell cycle checkpoint inhibitors, and other drugs can improve the treatment of endometrial cancer.
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Affiliation(s)
- Ke Shen
- The Third Affiliated Hospital of Zhengzhou University, Obstetrics, and Gynecology, China
| | - Li Yang
- The Third Affiliated Hospital of Zhengzhou University, Obstetrics, and Gynecology, China
| | - Fei-Yan Li
- The Third Affiliated Hospital of Zhengzhou University, Obstetrics, and Gynecology, China
| | - Feng Zhang
- The Third Affiliated Hospital of Zhengzhou University, Obstetrics, and Gynecology, China
| | - Lei-Lei Ding
- The Third Affiliated Hospital of Zhengzhou University, Obstetrics, and Gynecology, China
| | - Jing Yang
- The Third Affiliated Hospital of Zhengzhou University, Obstetrics, and Gynecology, China
| | - Jie Lu
- The Third Affiliated Hospital of Zhengzhou University, Obstetrics, and Gynecology, China
| | - Nan-Nan Wang
- The Third Affiliated Hospital of Zhengzhou University, Obstetrics, and Gynecology, China
| | - Yan Wang
- The Third Affiliated Hospital of Zhengzhou University, Obstetrics, and Gynecology, China
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Ma J, Yang D, Ma XX. Immune infiltration-related N6-methyladenosine RNA methylation regulators influence the malignancy and prognosis of endometrial cancer. Aging (Albany NY) 2021; 13:16287-16315. [PMID: 34230220 PMCID: PMC8266343 DOI: 10.18632/aging.203157] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 05/11/2021] [Indexed: 12/11/2022]
Abstract
N6-methyladenosine (m6A) RNA methylation is associated with malignant tumor progression and is modulated by various m6A RNA methylation regulator proteins. However, its role in endometrial cancer is unclear. In this work, we analyzed sequence, copy number variation, and clinical data obtained from the TCGA database. Expression was validated using real-time quantitative polymerase chain reaction and immunohistochemistry. Changes in m6A RNA methylation regulators were closely related to the clinicopathological stage and prognosis of endometrial cancer. In particular, ZC3H13, YTHDC1, and METTL14 were identified as potential markers for endometrial cancer diagnosis and prognosis. The TIMER algorithm indicated that immune cell infiltration correlated with changes in ZC3H13, YTHDC1, and METTL14 expression. Meanwhile, ZC3H13 or YTHDC1 knockdown promoted the proliferation and invasion of endometrial cancer cells. Through gene enrichment analysis, we constructed a regulatory network in order to explore the potential molecular mechanism involving ZC3H13, YTHDC1, and METTL14. Virtual screening predicted interactions of potential therapeutic compounds with METTL14 and YTHDC1. These findings advance the understanding of RNA epigenetic modifications in endometrial cancer while identifying m6A regulators associated with immune infiltration, prognosis, and potential treatment strategies.
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Affiliation(s)
- Jian Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Di Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xiao-Xin Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
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27
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Ono K, Kasajima R, Katayama K, Miyagi Y, Yokose T. Clinicopathological and molecular characteristics of endometrial neuroendocrine carcinomas reveal preexisting endometrial carcinoma origin. Pathol Int 2021; 71:491-499. [PMID: 34015161 DOI: 10.1111/pin.13108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/22/2021] [Indexed: 02/05/2023]
Abstract
Endometrial neuroendocrine carcinoma is a rare disease with unknown clinicopathological and molecular characteristics. Therefore, we conducted the present study to elucidate the clinicopathological and molecular characteristics of endometrial neuroendocrine carcinoma, as compared to conventional endometrial carcinoma, and to determine the origin of the former. We analyzed 22 endometrial neuroendocrine carcinomas and 22 conventional endometrial neoplasia cases with respect to clinical, histological and genetic features. Of these, 21/22 neuroendocrine carcinoma cases were admixed carcinomas, with 15 admixed with endometrioid adenocarcinoma. Genetic analysis of hotspot mutations in 50 cancer-related genes revealed that the neuroendocrine carcinoma group carried mutations in PIK3CA (12/22 cases; 54%) and PTEN (8/22 cases; 36%), commonly encountered in endometrioid adenocarcinoma. Comparative statistical analysis of neuroendocrine carcinoma and conventional endometrial neoplasia cases showed a significant trend only in PIK3CA mutation. Moreover, in six mixed-type neuroendocrine carcinoma cases, macrodissection was used to separate the neuroendocrine carcinoma and endometrioid adenocarcinoma components for next-generation sequencing, which revealed several mutations common among the two. These findings suggest that endometrial neuroendocrine carcinoma could originate from conventional endometrial neoplasia, especially endometrioid adenocarcinoma.
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Affiliation(s)
- Kyoko Ono
- Department of Pathology, Kanagawa Cancer Center, Kanagawa, Japan.,Department of Clinical Pathology, Yokohama Municipal Citizen's Hospital, Kanagawa, Japan.,Department of Molecular Pathology, Yokohama City University, Kanagawa, Japan
| | - Rika Kasajima
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Kanagawa, Japan
| | - Kayoko Katayama
- Unit of Cancer Survivorship and Education, Kanagawa Cancer Center Research Institute, Kanagawa, Japan
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Kanagawa, Japan
| | - Tomoyuki Yokose
- Department of Pathology, Kanagawa Cancer Center, Kanagawa, Japan
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28
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Thomas A, Reetz S, Stenzel P, Tagscherer K, Roth W, Schindeldecker M, Michaelis M, Rothweiler F, Cinatl J, Cinatl J, Dotzauer R, Vakhrusheva O, Albersen M, Macher-Goeppinger S, Haferkamp A, Juengel E, Neisius A, Tsaur I. Assessment of PI3K/mTOR/AKT Pathway Elements to Serve as Biomarkers and Therapeutic Targets in Penile Cancer. Cancers (Basel) 2021; 13:2323. [PMID: 34066040 PMCID: PMC8151654 DOI: 10.3390/cancers13102323] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 11/16/2022] Open
Abstract
The PI3K/mTOR/AKT pathway might represent an intriguing option for treatment of penile cancer (PeCa). We aimed to assess whether members of this pathway might serve as biomarkers and targets for systemic therapy. Tissue of primary cancer from treatment-naïve PeCa patients was used for tissue microarray analysis. Immunohistochemical staining was performed with antibodies against AKT, pAKT, mTOR, pmTOR, pS6, pPRAS, p4EBP1, S6K1 and pp70S6K. Protein expression was correlated with clinicopathological characteristics as well as overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and metastasis-free survival (MFS). AKT inhibition was tested in two primarily established, treatment-naïve PeCa cell lines by treatment with capivasertib and analysis of cell viability and chemotaxis. A total of 76 patients surgically treated for invasive PeCa were included. Higher expression of AKT was significantly more prevalent in high-grade tumors and predictive of DSS and OS in the Kaplan-Meier analysis, and an independent predictor of worse OS and DSS in the multivariate regression analysis. Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one.
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Affiliation(s)
- Anita Thomas
- Department of Urology and Pediatric Urology, University Medicine Mainz, 55122 Mainz, Germany; (A.T.); (S.R.); (R.D.); (O.V.); (S.M.-G.); (A.H.); (E.J.); (A.N.)
| | - Sascha Reetz
- Department of Urology and Pediatric Urology, University Medicine Mainz, 55122 Mainz, Germany; (A.T.); (S.R.); (R.D.); (O.V.); (S.M.-G.); (A.H.); (E.J.); (A.N.)
| | - Philipp Stenzel
- Department of Pathology, University Medicine Mainz, 55122 Mainz, Germany; (P.S.); (K.T.); (W.R.); (M.S.)
| | - Katrin Tagscherer
- Department of Pathology, University Medicine Mainz, 55122 Mainz, Germany; (P.S.); (K.T.); (W.R.); (M.S.)
| | - Wilfried Roth
- Department of Pathology, University Medicine Mainz, 55122 Mainz, Germany; (P.S.); (K.T.); (W.R.); (M.S.)
| | - Mario Schindeldecker
- Department of Pathology, University Medicine Mainz, 55122 Mainz, Germany; (P.S.); (K.T.); (W.R.); (M.S.)
| | - Martin Michaelis
- Industrial Biotechnology Centre and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK;
| | - Florian Rothweiler
- Institute of Medical Virology, Goethe-University, 60596 Frankfurt am Main, Germany; (F.R.); (J.C.J.); (J.C.)
| | - Jindrich Cinatl
- Institute of Medical Virology, Goethe-University, 60596 Frankfurt am Main, Germany; (F.R.); (J.C.J.); (J.C.)
| | - Jaroslav Cinatl
- Institute of Medical Virology, Goethe-University, 60596 Frankfurt am Main, Germany; (F.R.); (J.C.J.); (J.C.)
| | - Robert Dotzauer
- Department of Urology and Pediatric Urology, University Medicine Mainz, 55122 Mainz, Germany; (A.T.); (S.R.); (R.D.); (O.V.); (S.M.-G.); (A.H.); (E.J.); (A.N.)
| | - Olesya Vakhrusheva
- Department of Urology and Pediatric Urology, University Medicine Mainz, 55122 Mainz, Germany; (A.T.); (S.R.); (R.D.); (O.V.); (S.M.-G.); (A.H.); (E.J.); (A.N.)
| | - Maarten Albersen
- Department of Urology, University Hospitals Leuven, 3000 Leuven, Belgium;
| | - Stephan Macher-Goeppinger
- Department of Urology and Pediatric Urology, University Medicine Mainz, 55122 Mainz, Germany; (A.T.); (S.R.); (R.D.); (O.V.); (S.M.-G.); (A.H.); (E.J.); (A.N.)
| | - Axel Haferkamp
- Department of Urology and Pediatric Urology, University Medicine Mainz, 55122 Mainz, Germany; (A.T.); (S.R.); (R.D.); (O.V.); (S.M.-G.); (A.H.); (E.J.); (A.N.)
| | - Eva Juengel
- Department of Urology and Pediatric Urology, University Medicine Mainz, 55122 Mainz, Germany; (A.T.); (S.R.); (R.D.); (O.V.); (S.M.-G.); (A.H.); (E.J.); (A.N.)
| | - Andreas Neisius
- Department of Urology and Pediatric Urology, University Medicine Mainz, 55122 Mainz, Germany; (A.T.); (S.R.); (R.D.); (O.V.); (S.M.-G.); (A.H.); (E.J.); (A.N.)
- Department of Urology and Pediatric Urology, Krankenhaus der Barmherzigen Brüder Trier, 54292 Trier, Germany
| | - Igor Tsaur
- Department of Urology and Pediatric Urology, University Medicine Mainz, 55122 Mainz, Germany; (A.T.); (S.R.); (R.D.); (O.V.); (S.M.-G.); (A.H.); (E.J.); (A.N.)
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Tailored Therapy Based on Molecular Characteristics in Endometrial Cancer. BIOMED RESEARCH INTERNATIONAL 2021; 2021:2068023. [PMID: 34036097 PMCID: PMC8118729 DOI: 10.1155/2021/2068023] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 04/28/2021] [Indexed: 12/22/2022]
Abstract
Management of endometrial cancer, an adenocarcinoma of the endometrium which occupies most uterine corpus neoplasms, including uterine sarcomas, has been more relevant due to its increasing incidence. Extensive research on tumorigenesis molecular mechanisms and molecular characterization across cancers has brought paradigm shifts in the treatment of various malignant tumors. Endometrial cancer treatment has been traditionally guided according to the disease extent or histology types, while recent studies on molecular features have led to the introduction of targeted agents into clinical use, along with conventional chemotherapeutic agents in patients with recurrent or metastatic disease. Considering the proven efficacy and relatively tolerable toxicities of targeted therapies across malignant tumors, improvement of treatment outcomes is also expected in endometrial cancer by adopting an individualized therapy depending on the specific molecular features. Efficacy assessment of new biological agents is still ongoing based on previous preclinical data on endometrial cancer molecular features. Here, endometrial cancer molecular characterization will be reviewed, and then, we will introduce preclinical data, directing the adoption of new biological agents.
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Javadian P, Washington C, Mukasa S, Benbrook DM. Histopathologic, Genetic and Molecular Characterization of Endometrial Cancer Racial Disparity. Cancers (Basel) 2021; 13:cancers13081900. [PMID: 33920951 PMCID: PMC8071317 DOI: 10.3390/cancers13081900] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 03/30/2021] [Accepted: 04/12/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Black patients are diagnosed and die earlier of endometrial cancer in comparison with their White counterparts. Factors that have been implicated in this racial disparity, such as socioeconomic status, increased frequencies of more aggressive tumor histology, and comorbid conditions, do not account for all of the disparity. Molecular defects in the endometrial tumors likely also contribute to the more aggressive tumor biology and the patient disparities. In this study, we reviewed the published data of molecular characteristics of endometrial cancer in different races. The majority of the publications compare Black and White patients, and identify molecules and pathways that can be targeted with existing drugs. These findings encourage molecular profile studies comparing additional races and ethnicities, and development of race-specific treatments. Abstract In contrast to the decline in incidence and mortality of most other cancers, these rates are rising for endometrial cancer. Black women with endometrial cancer have earlier diagnosis, more aggressive histology, advanced stage and worse outcomes compared with their White counterparts. Socioeconomic status, a higher incidence of aggressive histology, and comorbid conditions are known factors leading to racial disparity in patients with endometrial cancer; nevertheless, they do not account for the entire racial disparity; which emphasizes the roles of molecular, histopathological and genetic factors. We performed a comprehensive review of all published scientific literature up to January 2021 reporting histopathologic, genetic and molecular factors associated with racial disparities in patients with endometrial cancer. The interactions and pathways of molecules reported to have significant differential expression in endometrial cancers from Black and White patients were identified with Ingenuity Pathway Analysis. The majority of studies compared Black and White patients; however, limited data are available for other racial and ethnic groups. Reported differences that could account for the worse survival of Black endometrial cancer patients include more aggressive histopathologies and molecular alterations, including upregulation of molecules driving cell cycle progression, and p53 and HER2/NEU signaling. Several of these molecules are targeted by existing pharmaceuticals. These findings encourage further study and the development of race-specific treatment strategies.
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Affiliation(s)
- Pouya Javadian
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
- Correspondence: (P.J.); (D.M.B.)
| | - Christina Washington
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Shylet Mukasa
- Arkansas College of Osteopathic Medicine, Fort Smith, AR 72916, USA;
| | - Doris Mangiaracina Benbrook
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
- Correspondence: (P.J.); (D.M.B.)
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Mazloumi Gavgani F, Karlsson T, Tangen IL, Morovicz AP, Arnesen VS, Turcu DC, Ninzima S, Spang K, Krakstad C, Guillermet-Guibert J, Lewis AE. Nuclear upregulation of class I phosphoinositide 3-kinase p110β correlates with high 47S rRNA levels in cancer cells. J Cell Sci 2021; 134:jcs.246090. [PMID: 33536247 DOI: 10.1242/jcs.246090] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 12/24/2020] [Indexed: 12/12/2022] Open
Abstract
The class I phosphoinositide 3-kinase (PI3K) catalytic subunits p110α and p110β are ubiquitously expressed but differently targeted in tumours. In cancer, PIK3CB (encoding p110β) is seldom mutated compared with PIK3CA (encoding p110α) but can contribute to tumorigenesis in certain PTEN-deficient tumours. The underlying molecular mechanisms are, however, unclear. We have previously reported that p110β is highly expressed in endometrial cancer (EC) cell lines and at the mRNA level in primary patient tumours. Here, we show that p110β protein levels are high in both the cytoplasmic and nuclear compartments in EC cells. Moreover, high nuclear:cytoplasmic staining ratios were detected in high-grade primary tumours. High levels of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P 3] were measured in the nucleus of EC cells, and pharmacological and genetic approaches showed that its production was partly dependent upon p110β activity. Using immunofluorescence staining, p110β and PtdIns(3,4,5)P 3 were localised in the nucleolus, which correlated with high levels of 47S pre-rRNA. p110β inhibition led to a decrease in both 47S rRNA levels and cell proliferation. In conclusion, these results present a nucleolar role for p110β that may contribute to tumorigenesis in EC.This article has an associated First Person interview with Fatemeh Mazloumi Gavgani, joint first author of the paper.
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Affiliation(s)
| | - Thomas Karlsson
- Department of Biological Sciences, University of Bergen, Bergen 5008, Norway
| | - Ingvild L Tangen
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.,Department of Gynaecology and Obstetrics, Haukeland University Hospital, Bergen 5021, Norway
| | | | | | - Diana C Turcu
- Department of Biological Sciences, University of Bergen, Bergen 5008, Norway
| | - Sandra Ninzima
- Department of Biological Sciences, University of Bergen, Bergen 5008, Norway
| | - Katharina Spang
- Department of Biological Sciences, University of Bergen, Bergen 5008, Norway
| | - Camilla Krakstad
- Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.,Department of Gynaecology and Obstetrics, Haukeland University Hospital, Bergen 5021, Norway
| | - Julie Guillermet-Guibert
- Inserm U1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III Paul Sabatier, 31037 Toulouse, France
| | - Aurélia E Lewis
- Department of Biological Sciences, University of Bergen, Bergen 5008, Norway
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Yue S, Li Y, Chen X, Wang J, Li M, Chen Y, Wu D. FGFR-TKI resistance in cancer: current status and perspectives. J Hematol Oncol 2021; 14:23. [PMID: 33568192 PMCID: PMC7876795 DOI: 10.1186/s13045-021-01040-2] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 02/01/2021] [Indexed: 02/07/2023] Open
Abstract
Fibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.
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Affiliation(s)
- Sitong Yue
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Yukun Li
- Clinical Anatomy and Reproductive Medicine Application Institute, Department of Histology and Embryology, Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, University of South China, Hengyang, 421001, China
| | - Xiaojuan Chen
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Juan Wang
- Clinical Anatomy and Reproductive Medicine Application Institute, Department of Histology and Embryology, Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, University of South China, Hengyang, 421001, China
| | - Meixiang Li
- Clinical Anatomy and Reproductive Medicine Application Institute, Department of Histology and Embryology, Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, University of South China, Hengyang, 421001, China
| | - Yongheng Chen
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Daichao Wu
- Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. .,Clinical Anatomy and Reproductive Medicine Application Institute, Department of Histology and Embryology, Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, University of South China, Hengyang, 421001, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. .,W.M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD, 20850, USA.
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Ma J, Zhang JK, Yang D, Ma XX. Identification of novel prognosis-related genes in the endometrial cancer immune microenvironment. Aging (Albany NY) 2020; 12:22152-22173. [PMID: 33159014 PMCID: PMC7695382 DOI: 10.18632/aging.104083] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 08/31/2020] [Indexed: 12/11/2022]
Abstract
The incidence of endometrial cancer is increasing each year, and treatment effects are poor for patients with advanced and specific subtypes. Exploring immune infiltration-related factors in endometrial cancer can aid in the prognosis of patients and provide new immunotherapy targets. We downloaded immune metagene and functional data of patients with different subtypes of endometrial cancer from The Cancer Genome Atlas database and selected the lymphocyte-specific kinase (LCK) metagene as a representative genetic marker of the immune microenvironment in endometrial cancer. The results showed that LCK metagene expression is related to the prognosis of patients with endometrioid endometrial adenocarcinoma subtypes and highly correlated with the PTEN and PIK3CA mutational status. A search for LCK-related modules returned seven independent genetic predictors of survival in patients with endometrial cancer. The TIMER algorithm showed that the expression of these seven genes was positively correlated with the infiltration levels of six types of immune cells. The diagnostic value of these markers was validated using real-time quantitative PCR and immunohistochemical methods. Our results identified CD74, HLA-DRB5, CD52, HLA-DPB1 and HLA-DRB1 as possible valuable genetic markers for the diagnosis and prognosis of endometrial cancer and provided a theoretical basis for immunotherapy targets for its clinical treatment.
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Affiliation(s)
- Jian Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Jing-Kai Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Di Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xiao-Xin Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
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Al Zoubi MS, Otoum R, Alorjani MS, Al Bashir S, Al Trad B, Abualrja MI, Al-Khatib SM, Al-Batayneh K. TP53, SPOP and PIK3CA Genes Status in Prostate Cancer. Asian Pac J Cancer Prev 2020; 21:3365-3371. [PMID: 33247697 PMCID: PMC8033120 DOI: 10.31557/apjcp.2020.21.11.3365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 11/24/2020] [Indexed: 11/25/2022] Open
Abstract
Recent advances in molecular biology make the identification of prostate cancer (PC) subsets a priority for more understanding of the molecular pathogenesis and treatment options. Genetic alterations in many genes such as TP53, SPOP and PIK3CA genes have been reported in PC with variable frequencies worldwide. We aimed to investigate genetic alterations in the hotspot lesions of TP53, SPOP and PIK3CA genes by direct sequencing and the expression of TP53 and PIK3CA by RT-PCR in prostate cancer, and to explore the correlation between TP53, SPOP and PIK3CA alterations and tumorigenesis of prostate cancer. Seventy-nine FFPE prostate samples from patients who underwent radical prostatectomy were obtained, subjected to genomic DNA extraction and sequenced for mutations in exons 5, 6, 7 and 8 of TP53 gene, exons 4 and 5 of SPOP gene and exons 9 and 20 of PIK3CA gene. RT-PCR was performed for the expression evaluation of the PIK3CA gene. Our results showed a high frequency of TP53 mutations (11/79, 13.9 %) in the selected population. On the other hand, SPOP and PIK3CA genes did not show any genetic alteration in the sequenced exons. PIK3CA gene overexpression was detected in 6% of the cohort by RT-PCR. TP53 mutation is the most frequent genetic alteration and likely has a major role in the pathogenesis of PC in the Jordanian population.
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Affiliation(s)
- Mazhar Salim Al Zoubi
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 211-63, Jordan.
| | - Raed Otoum
- Department of Biological Sciences, Faculty of Science, Yarmouk University, Irbid 211-63, Jordan.
| | - Mohammed S Alorjani
- Departments of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.
| | - Samir Al Bashir
- Departments of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.
| | - Bahaa Al Trad
- Department of Biological Sciences, Faculty of Science, Yarmouk University, Irbid 211-63, Jordan.
| | - Manal Issam Abualrja
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 211-63, Jordan.
| | - Sohaib M Al-Khatib
- Departments of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.
| | - Khalid Al-Batayneh
- Department of Biological Sciences, Faculty of Science, Yarmouk University, Irbid 211-63, Jordan.
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Chen N, Zhang W, Tang X, Ming Z, Xiao X. Branch migration-based polymerase chain reaction combined with endonuclease IV-assisted target recycling probe/blocker system for detection of low-abundance point mutations. Analyst 2020; 145:1355-1361. [PMID: 31970369 DOI: 10.1039/c9an02209k] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Sensitive detection of low-abundance point mutations in blood or tissue may provide a great opportunity for the minimally invasive diagnosis of cancer and other related diseases. We demonstrate a novel method for ultra-sensitive detection of point mutations at low abundance by combination of branch migration-based PCR with endonuclease IV-assisted target recycling probe/blocker system. The method is able to identify the point mutations at abundances down to 0.01-0.02%. We anticipate this method to be widely adopted in clinical diagnosis and molecular research.
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Affiliation(s)
- Na Chen
- Institute of Reproductive Health, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
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Shen HB, Li J, Yao YS, Yang ZH, Zhou YJ, Chen W, Hu TJ. Impact of Somatic Mutations in Non-Small-Cell Lung Cancer: A Retrospective Study of a Chinese Cohort. Cancer Manag Res 2020; 12:7427-7437. [PMID: 32884354 PMCID: PMC7443461 DOI: 10.2147/cmar.s254139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022] Open
Abstract
Background Somatic mutations are important biomarkers for selecting an optimal targeted therapy and predicting outcomes for non-small-cell lung cancer (NSCLC) patients that are often detected from tissue samples. However, tissue samples are not always readily available from these patients. The exploration of using circulating tumor DNA (ctDNA) to identify somatic mutations offers an alternative source that should be explored. Methods In this retrospective study, we included 280 patients diagnosed with adenocarcinoma between 2017 and 2018 in a hospital in eastern China. Tissue or ctDNA was collected, and a wide spectrum of somatic mutations was analyzed by targeted next-generation sequencing platforms. Associations among the mutation status, biomarkers, screening methods, disease stages, and interaction with treatment with overall survival (OS) were investigated. Results We found that the EGFR L858R mutation was the most frequently identified mutation in adenocarcinoma in this population by both methods, followed by KRAS (p=3.7e-09), PIK3CA (p=5e-04), and HER2 mutations (p=6.3e-03). We observed that EGFR mutations were significantly mutually exclusive with KRAS, HER2, and MET. FGFR1 mutations were significantly more abundantly detected in the ctDNA group. We found an interaction effect between EGFR mutation and target therapies. The ability of the targeted therapy to improve OS in patients with a single EGFR mutation (HR=0.069, p=0.07) approached significance, but this was not the case for the patients with more than one EGFR mutation or without an EGFR mutation (HR=0.813, p=0.725). Furthermore, the effect of chemotherapy was more predominant in the EGFR group in comparison to the control group. Conclusion These findings provide useful information on the distribution of somatic mutations via different screening methods and how this related to the optimal treatment selection in Chinese patients with NSCLC.
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Affiliation(s)
- Hai-Bo Shen
- Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, People's Republic of China
| | - Jie Li
- Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, People's Republic of China
| | - Yuan-Shan Yao
- Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, People's Republic of China
| | - Zhen-Hua Yang
- Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, People's Republic of China
| | - Yin-Jie Zhou
- Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, People's Republic of China
| | - Wei Chen
- Zhongyuan Union Clinical Laboratory Co., Ltd, Tianjin, People's Republic of China
| | - Tian-Jun Hu
- Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, People's Republic of China
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Musacchio L, Caruso G, Pisano C, Cecere SC, Di Napoli M, Attademo L, Tambaro R, Russo D, Califano D, Palaia I, Muzii L, Benedetti Panici P, Pignata S. PARP Inhibitors in Endometrial Cancer: Current Status and Perspectives. Cancer Manag Res 2020; 12:6123-6135. [PMID: 32801862 PMCID: PMC7383016 DOI: 10.2147/cmar.s221001] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 07/08/2020] [Indexed: 12/24/2022] Open
Abstract
Advanced, recurrent and metastatic endometrial cancer (EC) has a dismal prognosis due to poor response rates to conventional treatments. In the era of precision medicine, the improved understanding of cancer genetics and molecular biology has led to the development of targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. This class of drugs that inhibit PARP enzymes has been investigated in many different types of tumors and its use in the treatment of gynecological malignancies has rapidly increased over the past few years. Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA recombination system, regardless of the BRCA mutational status. Since EC frequently shows mutations in PTEN and TP53 genes, indirectly involved in the homologous DNA recombination pathway, several in vivo and in vitro studies investigated the efficacy of PARP inhibitors in EC, showing promising results. This review will discuss the use of PARP inhibitors in endometrial cancer, summarizing data from preclinical studies and providing an overview of the ongoing trials, with a special focus on the development of combined treatment strategies with PARP inhibitors and immune checkpoint inhibitors.
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Affiliation(s)
- Lucia Musacchio
- Department of Maternal and Child Health and Urological Sciences, University "Sapienza", Policlinico Umberto I, Rome, Italy
| | - Giuseppe Caruso
- Department of Maternal and Child Health and Urological Sciences, University "Sapienza", Policlinico Umberto I, Rome, Italy
| | - Carmela Pisano
- Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Sabrina Chiara Cecere
- Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Marilena Di Napoli
- Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Laura Attademo
- Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Rosa Tambaro
- Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Daniela Russo
- Functional Genomic Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Daniela Califano
- Functional Genomic Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Innocenza Palaia
- Department of Maternal and Child Health and Urological Sciences, University "Sapienza", Policlinico Umberto I, Rome, Italy
| | - Ludovico Muzii
- Department of Maternal and Child Health and Urological Sciences, University "Sapienza", Policlinico Umberto I, Rome, Italy
| | - Pierluigi Benedetti Panici
- Department of Maternal and Child Health and Urological Sciences, University "Sapienza", Policlinico Umberto I, Rome, Italy
| | - Sandro Pignata
- Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
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Kim B, Kang SY, Kim D, Heo YJ, Kim KM. PTEN Protein Loss and Loss-of-Function Mutations in Gastric Cancers: The Relationship with Microsatellite Instability, EBV, HER2, and PD-L1 Expression. Cancers (Basel) 2020; 12:cancers12071724. [PMID: 32610572 PMCID: PMC7407887 DOI: 10.3390/cancers12071724] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 06/25/2020] [Indexed: 12/21/2022] Open
Abstract
Inactivation of phosphatase and tensin homolog (PTEN) is caused by multiple mechanisms, and loss of PTEN activity is related to the progression of various cancers. In gastric cancer (GC), the relationship between the loss of PTEN protein expression and various genetic alterations remains unclear. The effects of microsatellite instability (MSI), Epstein–Barr virus (EBV), HER2 overexpression, and PD-L1 expression on PTEN mutation have not been fully explored. We performed comprehensive cancer panel tests with a cohort of 322 tumor samples from patients with advanced GC. Immunohistochemistry for PTEN protein was performed in all cases, and the loss of protein expression was defined as a complete absence of nuclear staining. In total, 34 cases (10.6%) had pathogenic PTEN mutations, of which 19 (55.9%) showed PTEN protein loss. The most common PTEN variants associated with protein loss were p.R130 (n = 4) followed by p.R335, p.L265fs, and deletions (n = 2). All the ten nonsense mutations identified in the samples resulted in PTEN inactivation. In the remaining 288 GC cases with wild-type PTEN, protein loss was found in 35 cases (12.2%). Thus, PTEN mutations were significantly associated with PTEN protein loss (p = 5.232 × 10−10), high MSI (p = 3.936 × 10−8), and EBV-positivity (p = 0.0071). In conclusion, our results demonstrate that loss-of-function mutations in PTEN are a frequent genetic mechanism of PTEN inactivation in GC.
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Affiliation(s)
- Binnari Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (B.K.); (S.Y.K.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
- Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (B.K.); (S.Y.K.)
| | - Deokgeun Kim
- Department of Clinical Genomics, Samsung Medical Center, Seoul 06351, Korea;
| | - You Jeong Heo
- The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (B.K.); (S.Y.K.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
- Correspondence: ; Tel.: +82-2-3410-2807; Fax: +82-2-3410-6396
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Differences in the molecular profile of endometrial cancers from British White and British South Asian women. PLoS One 2020; 15:e0233900. [PMID: 32520976 PMCID: PMC7286498 DOI: 10.1371/journal.pone.0233900] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 05/15/2020] [Indexed: 12/30/2022] Open
Abstract
Objectives To identify differences in the mutational profile of endometrial tumours between British White (BW) and South Asian (BSA) women. Methods We analysed primary tumours from matched cohorts of British White (BW) and British South Asian (BSA) women resident in Leicestershire diagnosed with EC. Next Generation Sequencing was performed to investigate mutational differences in a panel of 10 genes previously identified as being commonly mutated in EC. The presence of somatic Mismatch Repair (MMR) gene deficiencies was determined by immunohistochemistry. Results In total, 57 tumours (27 BSA and 30 BW) were sequenced. There was no significant difference in the overall mutation frequency of the 10 genes analysed; however, numerous differences were observed between the groups. There was a positive association between PIK3CA and PTEN mutations in the BSA group, with 78% of PIK3CA-mutant tumours harbouring a PTEN mutation, whereas only 11% of PIK3CA wild-type (wt) tumours were PTEN mutant positive (p = 0.0012). In BW women, 90% of ARID1A mutant tumours had co-existent PI3K pathway mutations versus 50% of wild-type (wt) ARID1A patients (p = 0.0485). This trend was not significant in the BSA group (p = 0.66). The age at diagnosis was significantly higher in the BW group with a somatic MMR gene deficiency compared to those with no deficiency (72.8 years versus 59.6 years, p = 0.007), whereas this difference was not seen in the BSA group (64 years versus 60 years, p = 0.37). Conclusion We have identified differences in the mutational profile of primary EC tumours from BW and BSA women. Further research is needed to confirm these findings and to explore their potential implications for early detection, treatment response and prognosis.
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40
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Design, synthesis, antitumor activity and theoretical calculation of novel PI3Ka inhibitors. Bioorg Chem 2020; 98:103737. [DOI: 10.1016/j.bioorg.2020.103737] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 03/05/2020] [Accepted: 03/07/2020] [Indexed: 01/03/2023]
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Dedifferentiated Carcinoma of the Endometrium Associated With Low-grade Müllerian Adenosarcoma. Int J Gynecol Pathol 2020; 39:141-145. [DOI: 10.1097/pgp.0000000000000584] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Haefliger S, Marston K, Juskevicius D, Meyer-Schaller N, Forster A, Nicolet S, Komminoth P, Stauffer E, Cathomas G, Hoeller S, Tornillo L, Dirnhofer S, Terracciano LM, Bihl M, Matter MS. Molecular Profile of Gastrointestinal Stromal Tumors in Sixty-Eight Patients from a Single Swiss Institution. Pathobiology 2020; 87:171-178. [PMID: 32079019 DOI: 10.1159/000505407] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 12/12/2019] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. It has distinct molecular features and primarily affects the KIT and PDGFRA genes. OBJECTIVE We wanted to assess the molecular profile of 68 GIST patients who were sequenced consecutively between 2014 and 2019 at our institute of pathology. METHODS Our cohort comprised 60 primary and 8 metastatic GIST patients; 43 and 57% of the cases, respectively, were analyzed by Sanger sequencing or next-generation sequencing (NGS). RESULTS Of the 60 primary GIST patients, 47 (78%) showed a KIT mutation; 2 cases showed a double KIT mutation, and 1 of these was a therapy-naive GIST. Nine (15%) patients harbored a PDGFRA mutation, 2 (3%) had a BRAF mutation, 1 (2%) had a PIK3CA mutation, and 1 (2%) did not show any mutation. One BRAF and the PIK3CA mutation have not been described in GIST before. All metastatic GIST harbored exclusively KIT mutations. CONCLUSION A retrospective analysis of GIST sequenced at our institute revealed incidences of KIT and PDGFRA mutations comparable to those in other cohorts from Europe. Interestingly, we found 2 previously undescribed mutations in the BRAF and PIK3CA genes as well as 1 treatment-naive case with a double KIT mutation in exon 11.
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Affiliation(s)
- Simon Haefliger
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | - Katharina Marston
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | - Darius Juskevicius
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | | | - Anja Forster
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | - Stefan Nicolet
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | - Paul Komminoth
- Institute of Pathology, Stadtspital Triemli, Zürich, Switzerland
| | - Edouard Stauffer
- Institute of Pathology, Promed Laboratoire Médical SA, Fribourg, Switzerland
| | - Gieri Cathomas
- Institute of Pathology, Kantonsspital Basel-Land, Liestal, Switzerland
| | - Sylvia Hoeller
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | - Luigi Tornillo
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | - Stefan Dirnhofer
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | | | - Michel Bihl
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | - Matthias S Matter
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland,
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Soliman PT, Westin SN, Iglesias DA, Fellman BM, Yuan Y, Zhang Q, Yates MS, Broaddus RR, Slomovitz BM, Lu KH, Coleman RL. Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study. Clin Cancer Res 2020; 26:581-587. [PMID: 31628143 PMCID: PMC7002216 DOI: 10.1158/1078-0432.ccr-19-0471] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 06/12/2019] [Accepted: 10/14/2019] [Indexed: 12/18/2022]
Abstract
PURPOSE Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second-line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent EEC. PATIENTS AND METHODS A Simon two-stage design was employed. Women with ≤2 prior chemotherapy regimens for recurrence were eligible. Pretreatment biopsy was required, followed by everolimus 10 mg orally, letrozole 2.5 mg orally, and metformin 500 mg orally twice a day on a 4-week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity. RESULTS Sixty-two patients were enrolled. Median age was 62 years (40-77) with 401 cycles completed, median of 6 cycles (1-31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received >12 cycles. Median follow-up was 17.9 months (2-47). Median progression-free survival was 5.7 [95% confidence interval (CI), 3.0-8.1] and OS was 19.6 months (95% CI, 14.2-26.3). Positive progesterone receptor expression was associated with CB (89.5% vs. 27.3%, P = 0.001). CONCLUSIONS Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor-positive tumors may have better response; validation studies are needed.See related commentary by Madariaga et al., p. 523.
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Affiliation(s)
- Pamela T Soliman
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.
| | - Shannon N Westin
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - David A Iglesias
- Department of Obstetrics and Gynecology, Virginia Tech Carilion School of Medicine, Roanoke, Virginia
| | - Bryan M Fellman
- Division of Biostatistics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Ying Yuan
- Division of Biostatistics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Qian Zhang
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Melinda S Yates
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Russell R Broaddus
- Department of Pathology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Brian M Slomovitz
- Sylvester Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Miller School of Medicine, University of Miami, Miami, Florida
| | - Karen H Lu
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Robert L Coleman
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
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Rubinstein MM, Hyman DM, Caird I, Won H, Soldan K, Seier K, Iasonos A, Tew WP, O'Cearbhaill RE, Grisham RN, Hensley ML, Troso-Sandoval T, Sabbatini P, Guillen J, Selcuklu SD, Zimel C, Torrisi J, Aghajanian C, Makker V. Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. Cancer 2019; 126:1274-1282. [PMID: 31880826 DOI: 10.1002/cncr.32677] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. METHODS We conducted a single-arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1-4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss-of-function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1. RESULTS Twenty-eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1-3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy-evaluable patients, the ORR was 16% (90% CI, 7%-100%), and the clinical benefit rate was 28% (90% CI, 16%-100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression-free survival and overall survival were 2.5 months (95% CI, 1.2-3.0) and 9.2 months (95% CI, 5.0-15.9), respectively. The most common all-grade treatment-related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed. CONCLUSION In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single-agent activity and a manageable safety profile.
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Affiliation(s)
- Maria M Rubinstein
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David M Hyman
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Imogen Caird
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Helen Won
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Krysten Soldan
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kenneth Seier
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Alexia Iasonos
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - William P Tew
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Roisin E O'Cearbhaill
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Rachel N Grisham
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Martee L Hensley
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Tiffany Troso-Sandoval
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Paul Sabbatini
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Joyce Guillen
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - S Duygu Selcuklu
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Catherine Zimel
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jean Torrisi
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Carol Aghajanian
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Vicky Makker
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
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Reijnen C, van der Putten LJM, Bulten J, Snijders MPLM, Küsters-Vandevelde HVN, Sweegers S, Vos MC, van der Wurff AAM, Ligtenberg MJL, Massuger LFAG, Eijkelenboom A, Pijnenborg JMA. Mutational analysis of cervical cytology improves diagnosis of endometrial cancer: A prospective multicentre cohort study. Int J Cancer 2019; 146:2628-2635. [PMID: 31523803 DOI: 10.1002/ijc.32686] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/16/2019] [Accepted: 08/30/2019] [Indexed: 01/06/2023]
Abstract
Endometrial carcinoma (EC) is traditionally diagnosed by a histopathological assessment of an endometrial biopsy, leaving up to 30% of patients undiagnosed due to technical failure or an inadequate amount of tissue. The aim of the current study is to assess whether mutational analysis of cervical cytology or pipelle endometrial biopsies improves the diagnostic accuracy of traditional histopathological diagnosis of EC. This prospective multicentre cohort study included patients surgically treated for EC or a benign gynaecological condition (control group). A Pap brush sample, cervicovaginal self-sample, pipelle endometrial biopsy and surgical specimen of either the EC or normal endometrium were obtained. A targeted next-generation sequencing panel was used to analyse these samples for mutations in eight genes. Sensitivity, specificity and predictive values were calculated. Fifty-nine EC patients and 31 control patients were included. In these patients, traditional histopathological diagnosis by pipelle had a sensitivity of 79% and a specificity of 100%. For EC patients, 97% of surgical specimens contained at least one mutation. Mutational analysis of Pap brush samples, self-samples and pipelle endometrial biopsies yielded a sensitivity of 78, 67 and 96% with a specificity of 97, 97 and 94%, respectively. Combining one of these three methods with histopathological pipelle endometrial biopsy evaluations yielded a sensitivity of 96, 93 and 96%, respectively. Our study has shown that mutational analysis of either cervical cytology or pipelle endometrial biopsies improves diagnosis of EC. Prospective validation will support implementation in clinical practice.
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Affiliation(s)
- Casper Reijnen
- Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands.,Department of Obstetrics and Gynaecology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands
| | - Louis J M van der Putten
- Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Johan Bulten
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Marc P L M Snijders
- Department of Obstetrics and Gynaecology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands
| | | | - Sanne Sweegers
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Maria C Vos
- Department of Obstetrics and Gynaecology, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands
| | | | - Marjolijn J L Ligtenberg
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.,Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Leon F A G Massuger
- Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Astrid Eijkelenboom
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Johanna M A Pijnenborg
- Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands
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Westin SN, Sill MW, Coleman RL, Waggoner S, Moore KN, Mathews CA, Martin LP, Modesitt SC, Lee S, Ju Z, Mills GB, Schilder RJ, Fracasso PM, Birrer MJ, Aghajanian C. Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An NRG Oncology/GOG study. Gynecol Oncol 2019; 155:420-428. [PMID: 31623857 DOI: 10.1016/j.ygyno.2019.09.024] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 11/25/2022]
Abstract
OBJECTIVE We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. METHODS Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). RESULTS Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0-15%) and 1 response in DL-1 (8.3%, 90%CI 0.4-33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. CONCLUSION The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.
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Affiliation(s)
- Shannon N Westin
- Department of Gynecologic Oncology, University of Texas M. D Anderson Cancer Center, USA.
| | - Michael W Sill
- NRG Oncology Statistics and Data Management Center Buffalo Office, Roswell Park Cancer Institute, USA.
| | - Robert L Coleman
- Department of Gynecologic Oncology, University of Texas M. D Anderson Cancer Center, USA.
| | - Steven Waggoner
- Department of Gynecologic Oncology, Case Western Reserve University, USA.
| | - Kathleen N Moore
- Department of Gynecologic Oncology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, USA.
| | - Cara A Mathews
- Department of Gynecologic Oncology, Women & Infants Hospital, USA.
| | - Lainie P Martin
- Department of Hematology/Oncology, Fox Chase Cancer Center, USA.
| | - Susan C Modesitt
- Director of Gynecologic Oncology Division, University of Virginia, USA.
| | - Sanghoon Lee
- Department of Medicine and the UVA Cancer Center, University of Virginia, USA.
| | - Zhenlin Ju
- Department of Bioinformatics and Computational Biology, University of Texas M. D Anderson Cancer Center, USA.
| | - Gordon B Mills
- Department of Medicine and the UVA Cancer Center, University of Virginia, USA.
| | - Russell J Schilder
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, USA.
| | - Paula M Fracasso
- Department of Systems Biology, University of Texas M.D Anderson Cancer Center, USA.
| | | | - Carol Aghajanian
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, USA.
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Straight C, Bradford L, Zweizig S. GYN ONCOLOGY. Cancer 2019. [DOI: 10.1002/9781119645214.ch19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Makii C, Ikeda Y, Oda K, Uehara Y, Nishijima A, Koso T, Kawata Y, Kashiyama T, Miyasaka A, Sone K, Tanikawa M, Tsuruga T, Mori-Uchino M, Nagasaka K, Matsumoto Y, Wada-Hiraike O, Kawana K, Hasegawa K, Fujiwara K, Aburatani H, Osuga Y, Fujii T. Anti-tumor activity of dual inhibition of phosphatidylinositol 3-kinase and MDM2 against clear cell ovarian carcinoma. Gynecol Oncol 2019; 155:331-339. [PMID: 31493899 DOI: 10.1016/j.ygyno.2019.08.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 08/15/2019] [Accepted: 08/23/2019] [Indexed: 12/19/2022]
Abstract
INTRODUCTION PI3K pathway signaling has received attention as a molecular target in clear cell ovarian carcinoma (CCOC). MDM2 is one of the AKT effectors in the PI3K pathway, which binds to and degrades p53. In this study, we aimed to clarify the prognostic significance of PIK3CA and MDM2 expression, and potential therapeutic effect of a dual inhibition of the PI3K pathway and MDM2. MATERIALS AND METHODS cDNA expression was evaluated by using microarray data using 75 samples of CCOC. DS-7423 (dual inhibitor of pan-PI3K and mTOR) and RG7112 (MDM2 inhibitor) were used on CCOC cell lines to evaluate cell proliferation, expression level of MDM2 related proteins, and apoptosis by MTT assay, western blotting, and flow cytometry. DS-7423 (3 mg/kg) and/or RG7112 (50 mg/kg) were orally administrated every day for three weeks, and the anti-tumor effect was evaluated using tumor xenografts, along with immunohistochemistry. RESULTS Tumors with high expression of both PIK3CA and MDM2 showed significantly worse prognosis in expression array of 71 CCOCs (P = 0.013). Dual inhibition of the PI3K pathway by DS-7423 and MDM2 by RG7112 showed synergistic anti-proliferative effect in 4 CCOC cell lines without TP53 mutations. The combination therapy more robustly induced pro-apoptotic proteins (PUMA and cleaved PARP) with increase of sub G1 population and apoptotic cells, compared with either single agent alone. The combination therapy significantly reduced tumor volume in mice (P < 0.001 in OVISE, and P = 0.038 in RMG-I) without severe body weight loss. Immunohistochemistry from the xenograft tumors showed that the combination treatment significantly reduced vascularity and cell proliferation, with an increase of apoptotic cell death. CONCLUSION A combination therapy targeting the PI3K pathway and MDM2 might be a promising therapeutic strategy in CCOC.
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Affiliation(s)
- Chinami Makii
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Yuji Ikeda
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan; Current address; Department of Obstetrics and Gynecology, Nihon University, Tokyo, Japan
| | - Katsutoshi Oda
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
| | - Yuriko Uehara
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan; Division of Genome Science, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Akira Nishijima
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan; Division of Genome Science, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Takahiro Koso
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan; Division of Genome Science, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Yoshiko Kawata
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Tomoko Kashiyama
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Aki Miyasaka
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Kenbun Sone
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Michihiro Tanikawa
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Tetsushi Tsuruga
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Mayuyo Mori-Uchino
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Kazunori Nagasaka
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Yoko Matsumoto
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Osamu Wada-Hiraike
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Kei Kawana
- Department of Obstetrics and Gynecology, Nihon University, Tokyo, Japan
| | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Keiichi Fujiwara
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Hiroyuki Aburatani
- Division of Genome Science, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
| | - Tomoyuki Fujii
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan
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Bilanges B, Posor Y, Vanhaesebroeck B. PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol 2019; 20:515-534. [PMID: 31110302 DOI: 10.1038/s41580-019-0129-z] [Citation(s) in RCA: 352] [Impact Index Per Article: 58.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PI3Ks are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3-phosphoinositide lipids, which directly activate signal transduction pathways. In addition to being frequently genetically activated in cancer, similar mutations in class I PI3Ks have now also been found in a human non-malignant overgrowth syndrome and a primary immune disorder that predisposes to lymphoma. The class II and class III PI3Ks are regulators of membrane traffic along the endocytic route, in endosomal recycling and autophagy, with an often indirect effect on cell signalling. Here, we summarize current knowledge of the different PI3K classes and isoforms, focusing on recently uncovered biological functions and the mechanisms by which these kinases are activated. Deeper insight into the PI3K isoforms will undoubtedly continue to contribute to a better understanding of fundamental cell biological processes and, ultimately, of human disease.
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Affiliation(s)
- Benoit Bilanges
- UCL Cancer Institute, University College London, London, UK.
| | - York Posor
- UCL Cancer Institute, University College London, London, UK.
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Abstract
Endometrial cancer accounts for ~76,000 deaths among women each year worldwide. Disease mortality and the increasing number of new diagnoses make endometrial cancer an important consideration in women's health, particularly in industrialized countries, where the incidence of this tumour type is highest. Most endometrial cancers are carcinomas, with the remainder being sarcomas. Endometrial carcinomas can be classified into several histological subtypes, including endometrioid, serous and clear cell carcinomas. Histological subtyping is currently used routinely to guide prognosis and treatment decisions for endometrial cancer patients, while ongoing studies are evaluating the potential clinical utility of molecular subtyping. In this Review, we summarize the overarching molecular features of endometrial cancers and highlight recent studies assessing the potential clinical utility of specific molecular features for early detection, disease risk stratification and directing targeted therapies.
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Affiliation(s)
- Mary Ellen Urick
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Daphne W Bell
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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