Kidney Cancer

Targeting HIF2 and VHL Synthetic Lethal Injections in Kidney Cancer

Project 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. 

Optimal Targeting of the PD-1/PD-L1 Pathway in MRCC

Project Summary

Anti-PD-1-based therapies have transformed the management of advanced renal cell carcinoma (RCC), leading to durable responses in a subset of patients. Despite this progress, the optimal therapeutic strategy (anti-PD-1 monotherapy versus dual checkpoint inhibition and dual checkpoint inhibition versus VEGF and PD-1 inhibition) for individual patients remains unclear, and too many patients still do not receive durable benefit from any of the PD-1 blockade-based therapies. Moving forward, the critical challenges are (i) how to best match a patient to an immunotherapy regimen, and (ii) understanding the key drivers and resistors of anti-RCC immunity following PD-1 blockade. Our unique access to a rich collection of samples from several front-line PD-1- blockade-based clinical trials and our comprehensive immunopathology and immunogenomics tool- kit for deeply dissecting the biologic features tumor cells and the immune microenvironment, uniquely position our group to address these challenges. To achieve the next paradigm shift in the treatment of patients with RCC, we hypothesize that an improved understanding of the expression state of RCC cells and their immune microenvironment at baseline provides critical information that will uncover targets for novel therapies and will rationally guide PD-1 blockade-based combinatorial therapy. 

We aim to clarify first-line therapy decisions by developing biomarkers for durable benefit from anti-PD-1 monotherapy, nivolumab/ipilimumab and axitinib/ pembrolizumab combination therapy using existing tissue collections, and then explore/confirm the value of these markers in the context of prospective phase III trials comparing the nivolumab/ipilimumab combination to either nivolumab monotherapy or axitinib/pembrolizumab. Ultimately, our efforts to establish a predictive model of durable benefit will help determine the appropriate RCC population to receive PD-1/CTLA-4 or PD-1/VEGF blockade, as well as unveil those patients who receive equal benefit from anti-PD-1 monotherapy or who require a different therapeutic approach. Moreover, we will use complementary analyses across patient samples to comprehensively characterize immune cell composition and functional state, determine target tumor antigens, and specific TCRs that mediate an effective anti-tumor response in RCC with the goal of ultimately developing novel immunotherapy approaches that enhance or induce specific and effective anti-tumor immunity. This work has the potential to optimize the application of currently effective anti-PD-1-based therapies for patients with advanced RCC and to provide new and effective immunotherapy approaches for those destined to not benefit optimally from current regimens.

HHLa2 as a Therapeutic Target in RCC

Project Summary

While immune checkpoint inhibitors (ICI) have revolutionized the treatment of many cancers, including metastatic clear cell renal cell carcinoma (ccRCC), the development of agents that overcome resistance to anti-PD-1/PD-L1 based therapy represents a critical unmet need for ccRCC patients. We have shown that the B7 family member HERV-H LTR-associating 2 (HHLA2) is expressed in the majority of ccRCC and recently have discovered an inhibitory receptor (KIR3DL3) for HHLA2. Monoclonal antibodies that selectively block the HHLA2/KIRDL3 interaction, which we call the HHLA2 Inhibitory Pathway (HIP), could be an important means to enhance anti-tumor immune responses. 

In this proposal, we will study the expression of HHLA2 and it receptors in kidney cancer on tumor cells and immune cells and the relationship of HHLA2 and PD-L1 expression on tumors cells. Using clinically annotated specimens from clinical trials of patients with ccRCC on anti-PD-1 therapy, we will determine whether HHLA2 expression is associated with lack of response to PD-1 therapy. We will elucidate the regulatory pathways that are similar and different between HHLA2 and PD-L1 to better understand the expression of these immune checkpoints in kidney cancer and how their expression may change over the course of tumor progression and selection pressures. We will identify the optimal reagents for activating T cells and NK cells through the HHLA2:KIR3DL3 pathway in both in vitro and in vivo models. Our results will direct the selection of humanized blocking antibodies of HHLA2 Inhibitory Pathway that will move into primate toxicity and human Phase I clinical trials during year two of this grant.