Novel Approaches to Targeting Cancers Associated with VHL Mutations

Division Of Basic Sciences - Nci

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Abstract

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 will be performed, including single agent studies in VHL patients, and single agent studies in sporadic ccRCC. Additionally, a variety of combination strategies will be evaluated in preclinical models and, if appropriate, in the clinic. Ongoing/planned studies include: 1) Evaluation of small molecule inhibitors of HIF2 alpha in VHL: The current management of patients with VHL associated malignancies involves surveillance and surgical/focal therapy to minimize the rsik of metastases and/or local complications. Patients with VHL undergo multiple surgical procedures during their lifetime with significant attendant morbidity. To explore systemic therapy alternatives to surgery, we conducted a phase 2 study of PT2385, a novel small molecule HIF2 inhibitor in patients with VHL associated renal tumors. Due to wide variability in pharmacokinetic parameters in patients enrolled on clinical trials of this agent, this study was halted after four patients were accrued, although encouraging signs of early activity were seen. A second generation, selective HIF2 -alpha inhibitor, PT2977, that is more potent than PT2385 and is associated with more predictable and uniform pharmacokinetics, was developed by our pharma collaborators for further clinical evaluation. I am co-leader of a new, multicenter, phase 2 study of this agent in VHL-associated RCC; our group was instrumental in helping design this study, which has completed accrual with patients currently undergoing treatment/evaluation on study. 2) Evaluation of HIF2-alpha inhibitors in sporadic ccRCC: A phase 2 study of PT2977 conducted by Peloton, Inc, in patients with advanced ccRCC who had progressed on prior immunotherapy and VEGFR targeted therapy revealed an ORR of 25%. The mechanisms underlying resistance to these agents is poorly understood at this time and warrant further study. Clinical studies to better understand the effects of PT2977 on tumors and the tumor microenvironment are under consideration as are preclinical studies to enable the development of rational, mechanism based combination approaches. This work will partly be done under the aegis of a UO1 grant developed with Dr. David McDermott and Dr. Marston Linehan: Developing a Translation Pipeline for VHL Mutant Malignancies (1U01CA236489-01).