2024 AACR-KidneyCAN Innovation and Discovery Grant Recipients
Edus H. Warren, MD, PhD
NCE 01.31.26
Validating shared endogenous retroviral T cell antigens in kidney cancer
Qing Zhang, PhD
08.01.24 – 07.31.25
Targeting acquired resistance to hypoxia inducible factor 2 alpha inhibition in kidney cancer
Proposed Work
Human endogenousretroviral (HERV) antigens are thought to drive the unexpectedly high response of clear cell renal cell carcinoma (ccRCC) to immune checkpoint inhibitors, despite its low mutation and neoantigen burden. Dr. Warren and his team aimed to characterize T-cell reactivity for hERV-encoded, HLA-A2 associated T-cell epitopes spontaneously arising in HLA-A2+ RCC patients and assess the anti-tumor potency of these T cells.
Anticipated Impact
If successful, these studies may help lay the groundwork for a potential new approach to kidney cancer treatment, based on cellular therapy or vaccination.
“Kidney cancer is known for its sensitivity to immune therapy and developing antigen-specific therapy for kidney cancer is a major focus of our laboratory. The AACR-KidneyCAN Kidney Cancer Innovation and Discovery Grant will support the development of immune therapy for kidney cancer that targets the protein products of human endogenous retroviruses.”
Proposed Work
Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is often associated with the inactivation of VHL protein, which leads to the stabilization and accumulation of HIF-2α protein. Although the HIF-2α inhibitor belzutifan has received FDA approval for the treatment of ccRCC patients, both intrinsic and adaptive resistance to this drug have been reported. Dr. Zhang sought to identify potential targetable pathways that may contribute to HIF-2α inhibitor resistance.
Project Findings
Dr. Zhang and his team identified PTGES as a context-dependent contributor to belzutifan resistance. This finding may help explain variable responses to HIF-2α inhibitors and highlight PTGES as a potential therapeutic target for a subset of patients.
“HIF-2α inhibitor Belzultifan was approved by the FDA to treat advanced RCC. However, both intrinsic and adaptive resistance was reported, posing critical clinical challenges. This award will help generate vital preliminary data on uncovering the mechanisms underlying drug resistance and developing alternative treatments for HIF-2α inhibitor-resistant patients in kidney cancer.”
Since 1993, the American Association for Cancer research has awarded more than $540 million in funds toward almost 1,000 different grants. In 2021, the AACR awarded over $7 million.
The ACCR supports grantees from the United States and abroad, at every career stage. These grants accelerate cancer research.
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