Characterization of Epigenetic and Metabolic Vulnerability in VHL-Deficient ccRCC and Its Therapeutic Potential
Abstract
The current proposal focuses on clear cell renal cell carcinoma (ccRCC) and addresses one of Fiscal Year 2022 Kidney Cancer Research Program Focus Areas, that is, develop novel therapeutic strategies for the treatment of kidney cancer, such as novel drug targets, therapeutic modalities and agents, treatment combinations and drug delivery systems. ccRCC accounts for more than 75% of all renal cancer cases but is currently incurable. Loss of the tumor suppressor gene VHL is a key feature in ccRCC, which results in activation of hypoxia-inducible factor (HIF) to drive tumor development. Targeting HIF signaling has been recently approved by the FDA as a first-line drug to treat ccRCC. However, a large population of ccRCC patients are resistant to this targeted therapy. Therefore, identification of alternative therapeutic approaches for ccRCC treatment is an unmet clinical need. Our recent studies identified a next-generation DNA methyltransferase inhibitor that could selectively kill VHL-deficient ccRCC cells. However, the underlying mechanism remains obscure. In the current proposal, we will perform preclinical studies to evaluate this selective killing approaches in clinically relevant VHL-deficient ccRCC models and investigate the underlying mechanism. These proposed studies are highly innovative because they are expected to define a specific therapeutic approach for the treatment of VHL-deficient ccRCC. The short-term outcomes of this project are to determine the therapeutic potential of DNA methyltransferase inhibitor and understand the mechanism behind this targeted therapy. The goal will be achieved based on our expertise and through close collaborations with Dr. James Brugarolas (an internationally recognized leader in kidney cancer and a director of the NCI kidney cancer SPORE), Dr. Ralph DeBerardinis (an expert in cancer metabolism), and Dr. Chao Xing (an expert in bioinformatics) at UT Southwestern. In the long term, successful completion of this project will yield a rational therapeutic option for killing the most common and currently incurable subset of kidney cancer in patients including Service Members, their Families, Veterans, and the American public in near future.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310863
Entities
People
- Weibo Luo
Organizations
- United States Army
- University of Texas Southwestern Medical Center