Targeting Genetic and Metabolic Alterations in Distinct Subtypes of Renal Cell Carcinoma
Renal cell carcinoma (RCC) is among the ten most common cancers in the United States. Over the last three decades it has become increasingly clear that kidney cancer is a heterogeneous group of malignancies with several histologically, clinically and genetically distinct variants recognized today. The current therapeutic armamentarium against metastatic RCC includes agents that target the vascular endothelial growth factor (VEGF) or mTOR pathways as well as immune checkpoint inhibitors. Despite this seeming plethora of treatment options, patients with metastatic disease are rarely cured. Furthermore, these agents are effective primarily against the clear cell variant of kidney cancer. Therefore, continued research into the critical molecular mechanisms driving RCC is clearly needed. Our group focuses on identifying therapeutically meaningful genetic and molecular pathways driving distinct subtypes of kidney cancer. The primary aim of this project is to better characterize these key pathways and to use this data to develop and evaluate effective, personalized, systemic therapy options for patients with RCC.
Novel Approaches to Targeting Cancers Associated with VHL Mutations
Clear cell renal cell cancer (ccRCC) is the most common kidney cancer subtype, accounting for 75-80% of all kidney cancer. Despite advances in targeted therapy and immunotherapy, metastatic ccRCC is largely incurable. Current treatment standards include agents targeting the VEGF pathway and PD1/PDL1 interactions. While response rates are high with these therapies, often used in combination, only a small proportion of patients achieve long-term complete responses. Approximately 90% of ccRCC are characterized by loss/inactivation of the VHL gene. One consequence of VHL inactivation is the upregulation of a group of transcriptionally active proteins normally regulated by ambient oxygen tension—the hypoxia inducible factors (HIF). HIF upregulation mediates transcriptional upregulation of a number of proangiogenic and growth factor genes, including VEGF, which is a current target for therapy in patients with advanced kidney cancer. We hypothesize that directly targeting HIF might be more effective in reversing the alterations induced by VHL inactivation. The primary aim of this project is to evaluate pharmacologic targeting of HIF2 alpha, singly and in combination with other agents, in patients with VHL-deficient kidney cancer.
Upregulation of HIF2 is well studied consequence of VHL inactivation and appears to be critical for development of sporadic ccRCC (somatic VHL alteration) as well as a variety of tumors in patients with VHL (germline VHL alterations). Recently, small molecule inhibitors of HIF2 have been evaluated preclinically and are currently undergoing clinical evaluation. To test the efficacy of HIF2 alpha inhibitors a number of clinical studies are planned, including single agent studies in VHL patients, and single agent studies in sporadic ccRCC patients. Additionally, a variety of combination strategies will be evaluated in preclinical models and, if appropriate, in the clinic.
Ramaprasad Srinivasan, M.D., Ph.D. is an internationally renowned physician-scientist in the field of kidney cancer. He is currently a Senior Investigator in the NCI intramural program and serves as the Head of the Molecular Cancer Section, Urologic Oncology Branch. Dr. Srinivasan leads the efforts to develop novel treatment strategies for patients with kidney cancer within the Urologic Oncology Branch and the Center for Cancer Research. His work is focused on developing and evaluating individualized, mechanism-based proof-of-concept studies based on the recognition that there are inherent genetic and molecular differences between various subtype of kidney cancer He has pioneered the evaluation of systemic treatment strategies in patients with von Hippel Lindau disease (VHL), and co-led an international study that led to the FDA approval of the HIF2 a inhibitor, belzutifan, heralding a paradigm shift in the management of VHL. His work has also led to the development of a new standard of care in patients with metastatic kidney cancer associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). He is currently investigating a variety of newer 'targeted' agents as well as novel immunotherapy approaches, in clear cell and papillary kidney cancer, as well as hereditary kidney cancer syndromes.
Dr. Srinivasan obtained his medical degree from the Bangalore Medical College in India and subsequently completed his Ph.D. in biomedical sciences at the University of Texas MD Anderson Cancer Center in Houston. He came to the NCI in 1999 after completing his internal medicine residency training at the University of Texas Health Science Center-Houston, to pursue a fellowship in medical oncology/hematology.
Dr.Srinivasan serves on numerous NIH and extramural committees and on the editorial board of several journals. He is an investigator on numerous clinical trials and has authored over a hundred scientific papers and book chapters. He is the recipient of two NCI Director’s awards, recognizing his contributions to the development of new treatments for patients with kidney cancer and promoting diversity, equity and inclusion in clinical trials.
- Ball MW, Singer EA, Srinivasan R. Renal cell carcinoma: molecular characterization and evolving treatment paradigms. Curr Opin Oncol. 2017.
- Shuch B, Agochukwu N, Ricketts CJ, Vocke CD, Gautam R, Merino M, Linehan WM, Srinivasan R. Vascular Endothelial Growth Factor Receptor-Targeted Therapy in Succinate Dehydrogenase C Kidney Cancer. J Clin Oncol. 2016;34(9):e76-9.
- Sourbier C, Ricketts CJ, Matsumoto S, Crooks DR, Liao PJ, Mannes PZ, Yang Y, Wei MH, Srivastava G, Ghosh S, Chen V, Vocke CD, Merino M, Srinivasan R, Krishna MC, Mitchell JB, Pendergast AM, Rouault TA, Neckers L, Linehan WM. Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell. 2014;26(6):840-850.
- Shuch B, Vourganti S, Ricketts CJ, Middleton L, Peterson J, Merino MJ, Metwalli AR, Srinivasan R, Linehan WM. Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol. 2014;32(5):431-7.
- Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, Rini BI, Srinivas S, Stein MN, Adams LM, Ottesen LH, Laubscher KH, Sherman L, McDermott DF, Haas NB, Flaherty KT, Ross R, Eisenberg P, Meltzer PS, Merino MJ, Bottaro DP, Linehan WM, Srinivasan R. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol. 2013;31(2):181-6.
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This page was last updated on Tuesday, September 26, 2023