Abstract Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is the initiating or “truncal” event in both the sporadic as well as hereditary type of clear cell renal cell carcinomas (ccRCCs) and VHL – associated tumors. pVHL forms an ubiquitin ligase complex that targets the HIF (Hypoxia-inducible Factor) transcription factor for proteasomal degradation when oxygen is available. Deregulation of HIF, and particularly HIF2α, drives pVHL-defective tumor formation in vivo. Drugs against the HIF-responsive gene product, VEGF, have been approved for the treatment of ccRCC, but are not curative and have only modest activity against VHL–associated tumors. Earlier work by DF/HCC and NCI investigators credentialed HIF2α as a driver in ccRCC and VHL disease and we have sought to bring HIF2α inhibitors to the clinic. Our collaboration on the UO1 grant entitled “Developing a translational pipeline for patients with VHL mutated malignancies” has served to enhance the understanding of this crucial transcription factor and facilitate clinical development of HIF2α inhibitors. Over the last four years, DF/HCC and NCI investigators co-led two studies of a first-in-class inhibitor belzutifan that established proof of concept that HIF2α can be drugged. In ccRCC, Dr. Choueiri led the trial that showed that belzutifan was well tolerated and clinically active in a subset of heavily pre-treated patients. Building on this work, Dr. Choueiri's leading the pivotal belzutifan trial in ccRCC patients who have failed standard therapy (NCT04195750). The UO1 supported work of the Kaelin Lab has led to belzutifan combination trials with approved drugs (e.g., NCT05468697). In a parallel effort, Drs. Linehan and Srinivasan led, and DF/HCC investigators participated in, the phase 1/2 clinical trial that led to the FDA approval of belzutifan in patients with VHL disease (NCT03401788). This rapid regulatory approval was made possible by an NCI comparison of the historical experience of patients in the NCI VHL Family Database to those treated with belzutifan at the NIH Clinical Research Center. This work elucidated the impact of targeting HIF2α in VHL mutation driven tumors. All of these projects were facilitated by close collaborations with patient advocates and industry colleagues at monthly UO1 meetings. In our current grant period, we have established a collection of precious, belzutifan-treated VHL and ccRCC patient tumor samples; obtained from clinical trials co-led by UO1 investigators; that will enhance our ability to execute our aims. Working in parallel with industry colleagues, our UO1 team will continue to pursue the identification of predictive and pharmacodynamic (PD) biomarkers that will enable the rational application of HIF2α inhibitors. Novel combination regimens will be studied in parallel clinical trials and pre-clinical models to facilitate translational research. The long-term significance and ultimate clinical impact of this work will be to identify new therapeutic strategies for patients with VHL–associated tumors.

Narrative This UO1 brings together a unique team of investigators in von Hippel-Lindau (VHL) mutant malignancies (e.g. clear cell Renal Cell Carcinoma (ccRCC)) to address key unanswered questions with high clinical impact. Despite the recent progress achieved by UO1 investigators and others, there remains an urgent unmet need for the development of novel combination therapeutic strategies and tissue-based biomarkers with which to optimize the clinical use of HIF2α inhibitors. The established pre-clinical and clinical research programs for the study of VHL/RCC at the NCI will continue to be a cornerstone of this renewal proposal.