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

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.