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Bray A, Sahai V. IDH Mutant Cholangiocarcinoma: Pathogenesis, Management, and Future Therapies. Curr Oncol 2025; 32:44. [PMID: 39851960 PMCID: PMC11763940 DOI: 10.3390/curroncol32010044] [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: 11/12/2024] [Revised: 01/09/2025] [Accepted: 01/16/2025] [Indexed: 01/26/2025] Open
Abstract
Mutations in isocitrate dehydrogenase (IDH) genes are among the most frequently encountered molecular alterations in cholangiocarcinoma (CCA). These neomorphic point mutations endow mutant IDH (mIDH) with the ability to generate an R-enantiomer of 2-hydroxyglutarate (R2HG), a metabolite that drives malignant transformation through aberrant epigenetic signaling. As a result, pharmacologic inhibition of mIDH has become an attractive therapeutic strategy in CCAs harboring this mutation. One such inhibitor, ivosidenib, has already undergone clinical validation and received FDA approval in this disease, but there is still much work to be done to improve outcomes in mIDH CCA patients. In this publication we will review the pathogenesis and treatment of mIDH CCA with special emphasis on novel agents and combinations currently under investigation.
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Affiliation(s)
| | - Vaibhav Sahai
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA;
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2
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Kumar M, Kumar A, Srivastav A, Ghosh A, Kumar D. Genomic and molecular landscape of gallbladder cancer elucidating pathogenic mechanisms novel therapeutic targets and clinical implications. Mutat Res 2024; 830:111896. [PMID: 39754821 DOI: 10.1016/j.mrfmmm.2024.111896] [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: 11/04/2024] [Revised: 12/19/2024] [Accepted: 12/19/2024] [Indexed: 01/06/2025]
Abstract
Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis, often diagnosed at advanced stages due to subtle early symptoms. Recent studies have provided a comprehensive view of GBC's genetic and mutational landscape, uncovering crucial pathways involved in its pathogenesis. Environmental exposures, particularly to heavy metals, have been linked to elevated GBC risk. Established signaling pathways, including hormonal, apoptotic, metabolic, inflammatory, and DNA damage repair pathways, are integral to GBC progression, and evidence points to the involvement of specific germline and somatic mutations in its development. Key mutations in genes such as KRAS, TP53, IDH1/2, ERBB, PIK3CA, MET, MYC, BRAF, MGMT, CDKN2A and p16 have been identified as contributors to tumorigenesis, with additional alterations including chromosomal aberrations and epigenetic modifications. These molecular insights reveal several potential therapeutic targets that could address the limited treatment options for GBC. Promising therapeutic avenues under investigation include immune checkpoint inhibitors, tyrosine kinase inhibitors, tumor necrosis factor-related apoptosis-inducing ligands (TRAIL), and phytochemicals. Numerous clinical trials are assessing the efficacy of these targeted therapies. This review provides a detailed examination of GBC's genetic and mutational underpinnings, highlighting critical pathways and emerging therapeutic strategies. We discuss the implications of germline and somatic mutations for early detection and individualized treatment, aiming to bridge current knowledge gaps. By advancing our understanding of GBC's molecular profile, we hope to enhance diagnostic accuracy and improve treatment outcomes, ultimately paving the way for precision medicine approaches in managing GBC.
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Affiliation(s)
- Manishankar Kumar
- School of Health Sciences and Technology, UPES, Dehradun, Uttarakhand 248007, India
| | - Arun Kumar
- Mahavir Cancer Institute and Research Centre, Phulwarisharif, Patna, Bihar 801505, India
| | - Abhinav Srivastav
- Mahavir Cancer Institute and Research Centre, Phulwarisharif, Patna, Bihar 801505, India
| | - Ashok Ghosh
- Mahavir Cancer Institute and Research Centre, Phulwarisharif, Patna, Bihar 801505, India
| | - Dhruv Kumar
- School of Health Sciences and Technology, UPES, Dehradun, Uttarakhand 248007, India.
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3
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Wang Y, Liu H, Zhang M, Xu J, Zheng L, Liu P, Chen J, Liu H, Chen C. Epigenetic reprogramming in gastrointestinal cancer: biology and translational perspectives. MedComm (Beijing) 2024; 5:e670. [PMID: 39184862 PMCID: PMC11344282 DOI: 10.1002/mco2.670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 07/03/2024] [Accepted: 07/08/2024] [Indexed: 08/27/2024] Open
Abstract
Gastrointestinal tumors, the second leading cause of human mortality, are characterized by their association with inflammation. Currently, progress in the early diagnosis and effective treatment of gastrointestinal tumors is limited. Recent whole-genome analyses have underscored their profound heterogeneity and extensive genetic and epigenetic reprogramming. Epigenetic reprogramming pertains to dynamic and hereditable alterations in epigenetic patterns, devoid of concurrent modifications in the underlying DNA sequence. Common epigenetic modifications encompass DNA methylation, histone modifications, noncoding RNA, RNA modifications, and chromatin remodeling. These modifications possess the potential to invoke or suppress a multitude of genes associated with cancer, thereby governing the establishment of chromatin configurations characterized by diverse levels of accessibility. This intricate interplay assumes a pivotal and indispensable role in governing the commencement and advancement of gastrointestinal cancer. This article focuses on the impact of epigenetic reprogramming in the initiation and progression of gastric cancer, esophageal cancer, and colorectal cancer, as well as other uncommon gastrointestinal tumors. We elucidate the epigenetic landscape of gastrointestinal tumors, encompassing DNA methylation, histone modifications, chromatin remodeling, and their interrelationships. Besides, this review summarizes the potential diagnostic, therapeutic, and prognostic targets in epigenetic reprogramming, with the aim of assisting clinical treatment strategies.
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Affiliation(s)
- Yingjie Wang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Hongyu Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Mengsha Zhang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Jing Xu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Liuxian Zheng
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Pengpeng Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Jingyao Chen
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Hongyu Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Chong Chen
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
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Wang Y, Jia S, Wang F, Jiang R, Yin X, Wang S, Jin R, Guo H, Tang Y, Wang Y. 3D-QSAR, Scaffold Hopping, Virtual Screening, and Molecular Dynamics Simulations of Pyridin-2-one as mIDH1 Inhibitors. Int J Mol Sci 2024; 25:7434. [PMID: 39000539 PMCID: PMC11242256 DOI: 10.3390/ijms25137434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/30/2024] [Accepted: 07/04/2024] [Indexed: 07/16/2024] Open
Abstract
Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure-activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was -93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.
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Affiliation(s)
- Yifan Wang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave, Xi'an-Xianyang New Economic Zone, Xianyang 712046, China
| | - Shunjiang Jia
- College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave, Xi'an-Xianyang New Economic Zone, Xianyang 712046, China
| | - Fan Wang
- Second Clinical Medical College, Shaanxi University of Chinese Medicine, Shiji Ave, Xi'an-Xianyang New Economic Zone, Xianyang 712046, China
| | - Ruizhe Jiang
- Second Clinical Medical College, Shaanxi University of Chinese Medicine, Shiji Ave, Xi'an-Xianyang New Economic Zone, Xianyang 712046, China
| | - Xiaodan Yin
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Shuo Wang
- College of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Ruyi Jin
- College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave, Xi'an-Xianyang New Economic Zone, Xianyang 712046, China
| | - Hui Guo
- College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave, Xi'an-Xianyang New Economic Zone, Xianyang 712046, China
| | - Yuping Tang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave, Xi'an-Xianyang New Economic Zone, Xianyang 712046, China
| | - Yuwei Wang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave, Xi'an-Xianyang New Economic Zone, Xianyang 712046, China
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Leowattana W, Leowattana T, Leowattana P. Paradigm shift of chemotherapy and systemic treatment for biliary tract cancer. World J Gastrointest Oncol 2023; 15:959-972. [PMID: 37389105 PMCID: PMC10302992 DOI: 10.4251/wjgo.v15.i6.959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/14/2023] [Accepted: 05/05/2023] [Indexed: 06/14/2023] Open
Abstract
Biliary tract cancers (BTC) are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens. For more than a decade, the combination of gemcitabine and cis-platin has served as the first-line standard treatment. There are few choices for second-line chemo-therapy. Targeted treatment with fibroblast growth factor receptor 2 inhibitors, neurotrophic tyrosine receptor kinase inhibitors, and isocitrate dehydrogenase 1 inhibitors has had important results. Immune checkpoint inhibitors (ICI) such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients. The TOPAZ-1 trial's outcome is encouraging, and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options. Newer targets and agents for existing goals are being studied, which may represent a paradigm shift in BTC management. Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications, the new category of drugs may occupy a significant role in BTC therapies.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
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Testa U, Pelosi E, Castelli G. The clinical value of identifying genetic abnormalities that can be targeted in cholangiocarcinomas. Expert Rev Anticancer Ther 2023; 23:147-162. [PMID: 36654529 DOI: 10.1080/14737140.2023.2170878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
INTRODUCTION Cholangiocarcinomas (CCAs) are a heterogenous group of epithelial malignancies originating at any level of the biliary tree and are subdivided according to their location into intrahepatic (iCCA) and extrahepatic (eCCA). AREAS COVERED This review provides an updated analysis of studies of genetic characterization of CCA at the level of gene mutation profiling, copy number alterations and gene expression, with definition of molecular subgroups and identification of some molecular biomarkers and therapeutic targets. EXPERT OPINION With the development of genetic sequencing, several driver mutations have been identified and targeted as novel therapeutic approaches, including FGFR2, IDH1, BRAF, NTRK, HER2, ROS, and RET. Furthermore, identification of the cellular and molecular structure of the tumor microenvironment has contributed to the development of novel therapies, such as tumor immunotherapy. Combination therapies of chemotherapy plus targeted molecules or immunotherapy are under evaluation and offer the unique opportunity to improve the outcomes of CCA patients with advanced disease.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore Di Sanità, Rome, Italy
| | - Elvira Pelosi
- Department of Oncology, Istituto Superiore Di Sanità, Rome, Italy
| | - Germana Castelli
- Department of Oncology, Istituto Superiore Di Sanità, Rome, Italy
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Zeng TM, Pan YF, Yuan ZG, Chen DS, Song YJ, Gao Y. Immune-related RNA signature predicts outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma. Front Immunol 2022; 13:943066. [PMID: 36159865 PMCID: PMC9501891 DOI: 10.3389/fimmu.2022.943066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundImmune checkpoint inhibitor (ICI)-combined chemotherapy in advanced intrahepatic cholangiocarcinoma has been proved to have more efficacy in a series of clinical trials. However, whether the tumor microenvironment (TME) plays a vital role in immune-combined therapy has not been rigorously evaluated.MethodsFirstly, we assayed the immunogenic properties of GEM-based chemotherapy. Then, 12 ICC patients treated with PD-1 inhibitor (sintilimab) combined with gemcitabine and cisplatin (GemCis) from a phase 2 clinical trial (ChiCTR2000036652) were included and their immune-related gene expression profiles were analyzed using RNA from baseline tumor samples. Immune-related signature correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in an ICC cohort with 26 patients. Multiplexed immunofluorescence (mIF) and flow cytometry (FCM) analysis were performed to evaluate the immune-related molecules with therapeutic outcomes.ResultsGEM-based chemotherapy induced immunogenic cell death of cholangiocarcinoma cells, together with increased CD274 expression. In an ICC cohort, we found that upregulation of immune-checkpoint molecules and immune response-related pathways were significantly related to better clinical outcome. On the contrary, baseline immune-cell proportions in tumor tissues did not show any correlation with clinical benefit between responders and non-responders. Immune-related signature (including six genes) correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in a small ICC cohort with 26 patients.ConclusionImmune-related RNA signature predicts the outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma, which could be tested as a biomarker for immune-chemotherapy in the future.
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Affiliation(s)
- Tian-mei Zeng
- School of Medicine, Tongji University, Shanghai, China
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yu-fei Pan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zhen-gang Yuan
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Dong-sheng Chen
- Jiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, China
| | - Yun-jie Song
- Jiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, China
| | - Yong Gao
- School of Medicine, Tongji University, Shanghai, China
- Department of Oncology, Shanghai East Hospital, Shanghai, China
- *Correspondence: Yong Gao,
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8
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Francis SS, Ostrom QT, Cote DJ, Smith TR, Claus E, Barnholtz-Sloan JS. The Epidemiology of Central Nervous System Tumors. Hematol Oncol Clin North Am 2022; 36:23-42. [PMID: 34801162 DOI: 10.1016/j.hoc.2021.08.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
This article reviews the current epidemiology of central nervous system tumors. Population-level basic epidemiology, nationally and internationally, and current understanding of germline genetic risk are discussed, with a focus on known and well-studied risk factors related to the etiology of central nervous system tumors.
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Affiliation(s)
- Stephen S Francis
- Department of Neurological Surgery, Division of Neuro and Molecular Epidemiology, University of California San Francisco School of Medicine, 1450 3rd Street, HD442, San Francisco, CA 94158, USA.
| | - Quinn T Ostrom
- Department of Neurosurgery, Duke University School of Medicine, 571 Research Drive, MSRB-1, Rm 442, Durham, NC 27710, USA
| | - David J Cote
- Department of Neurosurgery, Keck School of Medicine, University of Southern California, 1200 N State Street, Suite 3300, Los Angeles, CA 90033, USA
| | - Timothy R Smith
- Department of Neurosurgery, Computational Neuroscience Outcomes Center, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Avenue, Boston, MA 02115, USA
| | - Elizabeth Claus
- Department of Neurosurgery, Yale University, Yale School of Public Health, Brigham and Women's Hospital, 60 College Street, New Haven, CT 06510, USA
| | - Jill S Barnholtz-Sloan
- Center for Biomedical Informatics and Information Technology, Trans-Divisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), NCI Shady Grove, 9609 Medical Center Dr, Rockville, MD 20850, USA
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Wen X, Jin HY, Li M, Kim Y, Cho NY, Kwak Y, Bae JM, Lee HS, Kang GH. Methylation statuses of NCOR2, PARK2, and ZSCAN12 signify densities of tumor-infiltrating lymphocytes in gastric carcinoma. Sci Rep 2022; 12:862. [PMID: 35039565 PMCID: PMC8763922 DOI: 10.1038/s41598-022-04797-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 12/21/2021] [Indexed: 11/29/2022] Open
Abstract
Individual cell types of human tissues have their own CpG site methylation profiles, which might be utilized for the development of methylation markers to denote tumor-infiltrating lymphocytes (TILs). We aimed to develop DNA methylation markers that recapitulate the densities of TILs in gastric carcinoma (GC). Through genome-wide methylation profiling, NCOR2, PARK2, and ZSCAN12 were found to be highly methylated in CD3-positive and CD8-positive cells and rarely methylated in tumor cells. Scores of the three methylation markers were analyzed for their relationship with the overall survival and recurrence-free survival of patients with advanced GC (n = 471). The scores of three methylation markers were closely associated with densities of CD3-positive or CD8-positive cells at the tumor center or invasive front of GCs and found to be a significant prognostic factor in univariate analysis of overall survival and recurrence-free survival. In multivariate analysis, the highest score showed hazard ratios of 0.513 (CI 0.306–0.857) and 0.434 (CI 0.261–0.720) for overall survival and recurrence-free survival, respectively. The findings suggest that methylation markers signifying TILs might be utilized for the recapitulation of TIL density in GCs and serve as biomarkers for predicting prognosis in patients with GC.
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Affiliation(s)
- Xianyu Wen
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hye-Yeong Jin
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Meihui Li
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Younghoon Kim
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Nam-Yun Cho
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea. .,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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Paweł K, Maria Małgorzata S. CpG Island Methylator Phenotype-A Hope for the Future or a Road to Nowhere? Int J Mol Sci 2022; 23:ijms23020830. [PMID: 35055016 PMCID: PMC8777692 DOI: 10.3390/ijms23020830] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/01/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
The CpG island methylator phenotype (CIMP) can be regarded as the most notable emanation of epigenetic instability in cancer. Since its discovery in the late 1990s, CIMP has been extensively studied, mainly in colorectal cancers (CRC) and gliomas. Consequently, knowledge on molecular and pathological characteristics of CIMP in CRC and other tumour types has rapidly expanded. Concordant and widespread hypermethylation of multiple CpG islands observed in CIMP in multiple cancers raised hopes for future epigenetically based diagnostics and treatments of solid tumours. However, studies on CIMP in solid tumours were hampered by a lack of generalisability and reproducibility of epigenetic markers. Moreover, CIMP was not a satisfactory marker in predicting clinical outcomes. The idea of targeting epigenetic abnormalities such as CIMP for cancer therapy has not been implemented for solid tumours, either. Twenty-one years after its discovery, we aim to cover both the fundamental and new aspects of CIMP and its future application as a diagnostic marker and target in anticancer therapies.
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11
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Wintheiser G, Zemla T, Shi Q, Tran N, Prasai K, Tella SH, Mody K, Ahn D, Borad M, Bekaii-Saab T, Mahipal A. Isocitrate Dehydrogenase-Mutated Cholangiocarcinoma: Natural History and Clinical Outcomes. JCO Precis Oncol 2022; 6:e2100156. [PMID: 35005992 DOI: 10.1200/po.21.00156] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Clinical-pathologic features and natural history of patients with isocitrate dehydrogenase (IDH)-mutant intrahepatic cholangiocarcinoma (CCA) are not well characterized. Here, we sought to describe the natural history, clinical phenotype, and prognostic impact of advanced, IDH-mutated CCA. METHODS We conducted a multicentric, retrospective analysis of patients with IDH-mutated (IDH1 or IDH2) CCA between 2010 and 2020. Median overall survival (OS) and progression-free survival (PFS) analyses were performed using the Kaplan-Meier method. Chi-square test was used to analyze disease control rate (DCR) and overall response rate (ORR). Matched controls were used for comparing survival between patients with and without IDH mutations (mIDH). RESULTS Sixty-five patients with IDH-mutated CCA were included. All patients had intrahepatic CCA. On first-line chemotherapy, median OS and median PFS were 21.2 months and 8.3 months, respectively. Notably, median OS (32.4 v 19.5 months, P = .12) and PFS (18.0 v 8.0 months, P = .12) were not significantly affected by disease status at presentation (locally advanced v metastatic, respectively). Median OS was significantly longer in patients with mIDH (21.2 v 10.5 months; P < .01). First-line gemcitabine-containing regimens had a significantly higher DCR and ORR than non-gemcitabine-containing regimens (DCR: 75% v 33%, P = .01; ORR: 39% v 0%, P = .02). In patients receiving IDH inhibitor therapy, median PFS was 4.6 months with a DCR of 29%. CONCLUSION CCA with mIDH confers a unique subtype resulting in a better survival compared with that of counterparts. IDH inhibitors represent a promising therapeutic option in later lines of therapy in this subgroup.
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Affiliation(s)
| | - Tyler Zemla
- Division of Biostatistics, Mayo Clinic, Rochester, MN
| | - Qian Shi
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
| | - Nguyen Tran
- Department of Medical Oncology, Mayo Clinic, Rochester, MN
| | - Kritika Prasai
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | | | - Kabir Mody
- Division of Medical Oncology, Mayo Clinic, Jacksonville, FL
| | - Daniel Ahn
- Department Medical Oncology, Mayo Clinic, Phoenix, AZ
| | - Mitesh Borad
- Department Medical Oncology, Mayo Clinic, Phoenix, AZ
| | | | - Amit Mahipal
- Department of Medical Oncology, Mayo Clinic, Rochester, MN
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12
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Rimini M, Puzzoni M, Pedica F, Silvestris N, Fornaro L, Aprile G, Loi E, Brunetti O, Vivaldi C, Simionato F, Zavattari P, Scartozzi M, Burgio V, Ratti F, Aldrighetti L, Cascinu S, Casadei-Gardini A. Cholangiocarcinoma: new perspectives for new horizons. Expert Rev Gastroenterol Hepatol 2021; 15:1367-1383. [PMID: 34669536 DOI: 10.1080/17474124.2021.1991313] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. AREA COVERED In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations, which may have an interesting clinical application in the next future. EXPERT OPINION In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures, including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Puzzoni
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Federica Pedica
- Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
| | - Nicola Silvestris
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - Lorenzo Fornaro
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Eleonora Loi
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Oronzo Brunetti
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy
| | - Caterina Vivaldi
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Francesca Simionato
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Patrizia Zavattari
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Valentina Burgio
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Stefano Cascinu
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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13
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Prete MG, Cammarota A, D’Alessio A, Zanuso V, Rimassa L. Current options and future directions of systemic therapy for advanced biliary tract cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:416-433. [PMID: 36045701 PMCID: PMC9400707 DOI: 10.37349/etat.2021.00054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 09/09/2021] [Indexed: 11/19/2022] Open
Abstract
Biliary tract cancers (BTCs) are aggressive tumors arising from different portions of the biliary tree and classified according to the anatomical location in intrahepatic (i) cholangiocarcinoma (CCA, iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Due to their silent behavior, BTCs are frequently diagnosed at advanced stages when the prognosis is poor. The available chemotherapeutic options are palliative and unfortunately, most patients will die from their disease between 6 and 18 months from diagnosis. However, over the last decade, amounting interest has been posed on the genomic landscape of BTCs and deep-sequencing studies have identified different potentially actionable driver mutations. Hence, the promising results of the early phase clinical studies with targeted agents against isocitrate dehydrogenase (IDH) 1 mutation or fibroblast growth factor (FGF) receptor (FGFR) 2 aberrations inintrahepatic tumors, and other agents against humanepidermal growth factor receptor (HER) 2 overexpression/mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions or B-type Raf kinase (BRAF) mutations across different subtypes of BTCs, have paved the way for a "precision medicine" strategy for BTCs. Moreover, despite the modest results when used as monotherapy, beyond microsatellite instability-high (MSI-H) tumors, immune checkpoint inhibitors are being evaluated in combination with platinum-based chemotherapy, possibly further expanding the therapeutic landscape of advanced BTCs. This review aims to provide an overview of the approved systemic therapies, the promising results, and the ongoing studies to explore the current and future directions of advanced BTC systemic treatment.
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Affiliation(s)
- Maria Giuseppina Prete
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Antonio D’Alessio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
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14
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Fan C, Kam S, Ramadori P. Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer. Cancers (Basel) 2021; 13:cancers13205250. [PMID: 34680398 PMCID: PMC8534280 DOI: 10.3390/cancers13205250] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/13/2021] [Accepted: 10/16/2021] [Indexed: 12/28/2022] Open
Abstract
Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches.
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15
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Sinniah RS, Shapses MS, Ahmed MU, Babiker H, Chandana SR. Novel biomarkers for cholangiocarcinoma: how can it enhance diagnosis, prognostication, and investigational drugs? Part-1. Expert Opin Investig Drugs 2021; 30:1047-1056. [PMID: 34579607 DOI: 10.1080/13543784.2021.1985461] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION The development of novel biomarkers for cancer has exploded over the last decade with advances in novel technologies. Cholangiocarcinoma (CCA), a cancer of the bile ducts, has a dearth of strong disease and pathophysiology biomarkers, making early detection and prognostication a difficult task. AREAS COVERED In this comprehensive review, we discuss the spectrum of biomarkers for CCA diagnosis and prognostication. We elaborate on novel biomarker discovery through a comprehensive multi-omics approach. We also cover, how certain biomarkers may also serve as unique and potent targets for therapeutic development. EXPERT OPINION Despite the relatively poor diagnostic and prognostic performance of existing biomarkers for CCA, there is a vast range of novel biomarkers with exquisite diagnostic and prognostic performance for CCA in the pipeline. Moreover, these biomarkers may serve as potential targets for precision medicine. Existing strategies to target unique biomolecular classes are discussed, within the context of an overall 'omics' focused profiling strategy. Omics profiling will simultaneously allow for enhanced biomarker development and identification of unique subtypes of cholangiocarcinoma and how they are influenced by an individual's unique context. In this manner, patient management strategy and clinical trial design can be optimized to the individual.
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Affiliation(s)
- Ranu S Sinniah
- College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - Mark S Shapses
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | | | - Hani Babiker
- Department of Medicine, Division of Hematology-Oncology, Mayo Clinic, Jacksonville, Florida, USA
| | - Sreenivasa R Chandana
- Phase I Program, Start Midwest, Grand Rapids, MI, USA.,Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI, USA.,Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, USA
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16
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Pirozzi CJ, Yan H. The implications of IDH mutations for cancer development and therapy. Nat Rev Clin Oncol 2021; 18:645-661. [PMID: 34131315 DOI: 10.1038/s41571-021-00521-0] [Citation(s) in RCA: 199] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2021] [Indexed: 02/07/2023]
Abstract
Mutations in the genes encoding the cytoplasmic and mitochondrial forms of isocitrate dehydrogenase (IDH1 and IDH2, respectively; collectively referred to as IDH) are frequently detected in cancers of various origins, including but not limited to acute myeloid leukaemia (20%), cholangiocarcinoma (20%), chondrosarcoma (80%) and glioma (80%). In all cases, neomorphic activity of the mutated enzyme leads to production of the oncometabolite D-2-hydroxyglutarate, which has profound cell-autonomous and non-cell-autonomous effects. The broad effects of IDH mutations on epigenetic, differentiation and metabolic programmes, together with their high prevalence across a variety of cancer types, early presence in tumorigenesis and uniform expression in tumour cells, make mutant IDH an ideal therapeutic target. Herein, we describe the current biological understanding of IDH mutations and the roles of mutant IDH in the various associated cancers. We also present the available preclinical and clinical data on various methods of targeting IDH-mutant cancers and discuss, based on the underlying pathogenesis of different IDH-mutated cancer types, whether the treatment approaches will converge or be context dependent.
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Affiliation(s)
- Christopher J Pirozzi
- Department of Pathology, Duke University Medical Center, Durham, NC, USA. .,Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.
| | - Hai Yan
- Department of Pathology, Duke University Medical Center, Durham, NC, USA. .,Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.
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17
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Claus EB, Cannataro VL, Gaffney SG, Townsend JP. Environmental and sex-specific molecular signatures of glioma causation. Neuro Oncol 2021; 24:29-36. [PMID: 33942853 PMCID: PMC8730771 DOI: 10.1093/neuonc/noab103] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background The relative importance of genetic and environmental risk factors in gliomagenesis remains uncertain. Methods Using whole-exome sequencing data from 1105 adult gliomas, we evaluate the relative contribution to cancer cell lineage proliferation and survival of single-nucleotide mutations in tumors by IDH mutation subtype and sex. We also quantify the contributions of COSMIC cancer mutational signatures to these tumors, identifying possible risk exposures. Results IDH-mutant tumors exhibited few unique recurrent substitutions—all in coding regions, while IDH wild-type tumors exhibited many substitutions in non-coding regions. The importance of previously reported mutations in IDH1/2, TP53, EGFR, PTEN, PIK3CA, and PIK3R1 was confirmed; however, the largest cancer effect in IDH wild-type tumors was associated with mutations in the low-prevalence BRAF V600E. Males and females exhibited mutations in a similar set of significantly overburdened genes, with some differences in variant sites—notably in the phosphoinositide 3-kinase (PI3K) pathway. In IDH-mutant tumors, PIK3CA mutations were located in the helical domain for females and the kinase domain for males; variants of import also differed by sex for PIK3R1. Endogenous age-related mutagenesis was the primary molecular signature identified; a signature associated with exogenous exposure to haloalkanes was identified and noted more frequently in males. Conclusions Cancer-causing mutations in glioma primarily originated as a consequence of endogenous rather than exogenous factors. Mutations in helical vs kinase domains of genes in the phosphoinositide 3-kinase (PI3K) pathway are differentially selected in males and females. Additionally, a rare environmental risk factor is suggested for some cases of glioma—particularly in males.
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Affiliation(s)
- Elizabeth B Claus
- Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut.,Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut.,Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts
| | | | - Stephen G Gaffney
- Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut
| | - Jeffrey P Townsend
- Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut.,Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut
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18
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Cigliano A, Chen X, Calvisi DF. Current challenges to underpinning the genetic basis for cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:511-526. [PMID: 33888034 PMCID: PMC8173760 DOI: 10.1080/17474124.2021.1915128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/07/2021] [Indexed: 12/23/2022]
Abstract
AREAS COVERED This review provides an overview regarding the current scenario and knowledge of the CCA genomic landscape and the potentially actionable molecular aberrations in each CCA subtype. EXPERT OPINION The establishment and advances of high-throughput methodologies applied to genetic and epigenetic profiling are changing many cancer types' therapeutic landscape , including CCA.The large body of data generated must be interpreted appropriately and eventually implemented in clinical practice. The following advancements toward precision medicine in CCA management will require designing better clinical trials with improved methods to stratify biliary tumor patients.
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Affiliation(s)
- Antonio Cigliano
- Department of Medical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Italy
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA
| | - Diego F. Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
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19
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Chen S, Wang Y, Xiong Y, Peng T, Lu M, Zhang L, Guo Z. Wild-type IDH1 inhibits the tumor growth through degrading HIF-α in renal cell carcinoma. Int J Biol Sci 2021; 17:1250-1262. [PMID: 33867843 PMCID: PMC8040470 DOI: 10.7150/ijbs.54401] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 03/04/2021] [Indexed: 12/30/2022] Open
Abstract
The purpose of our study was to explore the effect and intrinsic mechanism of wild-type IDH1 and its substrate α-KG on renal cell carcinoma (RCC). IDH1 was observed lower expression in RCC cell lines. Phenotype experiment was carried out in the wild-type IDH1 and mutant IDH1R132H plasmid treated cell line. The results showed that the wild-type IDH1 could significantly inhibit the proliferation, migration and promote the apoptosis of RCC cell lines, which were consistent with the IDH1's substrate α-KG. The mutant IDH1R132H was found to lose this biological function of IDH1. Moreover, we verified the proliferation inhibition of IDH1 in vivo. In addition, we verified the correlation between IDH1 and hypoxia signal-related proteins in vitro and in vivo, specifically, IDH1 overexpression could significantly reduce the expression of HIF-1α and HIF-2α proteins and its downstream proteins (VEGF, TGF-α). Furthermore, we preliminarily verified the possibility of α-KG in the RCC's treatment by injecting α-KG into the xenograft model. α-KG significantly reduced tumor size and weight in tumor-bearing mice. This study provided a new therapeutic target and small molecule for the study of the treatment and mechanism of RCC.
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Affiliation(s)
- Song Chen
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yejinpeng Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yaoyi Xiong
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Tianchen Peng
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Mengxin Lu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Lian Zhang
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Zhongqiang Guo
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
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