# Developing a Translation Pipeline for VHL Mutant Malignancies

> **NIH NIH U01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $669,180

## Abstract

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 ident...

## Key facts

- **NIH application ID:** 10830083
- **Project number:** 2U01CA236489-05A1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** David McDermott
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $669,180
- **Award type:** 2
- **Project period:** 2019-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830083

## Citation

> US National Institutes of Health, RePORTER application 10830083, Developing a Translation Pipeline for VHL Mutant Malignancies (2U01CA236489-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10830083. Licensed CC0.

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