# Project 1:Targeting HIF2 and VHL Synthetic Lethal Interactions in Kidney Cancer

> **NIH NIH P50** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $284,061

## Abstract

Summary
 Inactivation of the VHL tumor suppressor gene is the initiating genetic event in most
clear cell renal cell carcinomas (ccRCCs) and increases the abundance of HIF2α, which drives
ccRCC growth. HIF2α inhibitors are active against some, but not all, VHL-/- ccRCCs in
preclinical models. In the last funding cycle we and others showed that HIF2 inhibitors (e.g.
PT2977) have promising antitumor activity in pretreated ccRCC patients. While the efficacy
signal seen with PT2977 has justified the launch of a pivotal trial that could lead to its regulatory
approval, some ccRCC patients fail to respond to HIF2 blockade. Moreover, the patients that
do respond to PT2977 monotherapy eventually relapse in most cases. We need biomarkers
that identify patients who are likely to respond to HIF2α inhibitors (predictive biomarkers) and to
understand the mechanisms of resistance to such agents. Finally, de novo and acquired
resistance is also a problem with standard of care kidney cancer therapies (e.g. VEGF
inhibitors). We therefore need new therapeutic targets in kidney cancer. Ideally, drugs against
these new targets would be active as single agents and could be combined with existing agents,
with the combinations increasing response rates and decreasing therapeutic resistance.
 Two genes are synthetically lethal with one another when mutation of either gene alone
is tolerated but inactivation of both genes causes cell death. This paradigm has been validated
in the clinic with the activity of PARP inhibitors against BRCA1 mutant tumors. In our last
funding cycle we discovered that VHL and CDK4/6 have a synthetic lethal relationship.
Moreover, we showed that the hyperdependence of VHL-/- ccRCC cells was NOT driven by
HIF2. In keeping with the latter, we showed that CDK4/6 inhibitors were active against VHL-/-
ccRCCs, irrespective of their HIF2 dependence, and enhanced the activity of PT2977 against
HIF2-dependent VHL-/- ccRCC.
 In aim 1 of this proposal we will conduct a phase 1/2 trial of the CDK4/6 inhibitor
abemaciclib, alone and in combination with PT2977. In aim 2 we will search for additional
genes that are synthetic lethal with VHL. We will leverage our ability to do synthetic lethal
screens in both human cells and drosophila cells as a means of identifying genetic interactions
that are likely to be robust. In aim 3 we will use genetic approaches to identify the mechanisms
by which cells become resistant to HIF2 inhibitors. This aim could eventually yield new ways of
predicting which ccRCC patients will respond to HIF2 inhibitors as well as new ways to
circumvent resistance.

## Key facts

- **NIH application ID:** 10206024
- **Project number:** 5P50CA101942-17
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** WILLIAM G. KAELIN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $284,061
- **Award type:** 5
- **Project period:** 2003-09-18 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206024

## Citation

> US National Institutes of Health, RePORTER application 10206024, Project 1:Targeting HIF2 and VHL Synthetic Lethal Interactions in Kidney Cancer (5P50CA101942-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10206024. Licensed CC0.

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