Leveraging Metabolic Reprogramming for Synthetic Lethality in Clear Renal Cell Carcinoma
Abstract
Our overall objective is to identify innovative combinational strategies for treatment of clear cell renal carcinoma (ccRCC). Our central hypothesis is that manipulation of amino acid metabolism will reprogram DNA damage response and repair (DDR) in ccRCC and lead to therapeutic vulnerability, which can be effectively targeted by DDR inhibitors. It is known that cancer metabolism affects DDR and, in turn, DDR can trigger cancer metabolic rewiring. What remains unknown is the extent to which manipulation of amino acid metabolism reprograms DDR. The proposed research is innovative, in our opinion, because it represents a substantive departure from the status quo by shifting focus to pharmacological manipulation of amino acid metabolism to uncover conditional synthetic lethality interaction for targeted therapy. This concept has not been explored previously in ccRCC. If successful, it is expected to open new research horizons, as therapeutic applications of DDR inhibitors will not be limited to the DDR-deficient population. The proposed research will make an original and important contribution toward advancing basic and translational kidney cancer research. The primary impact of our proposal relates to the clinical implementation of amino acid deprivation therapy and DDR inhibitors, harnessing a proven synthetic lethal therapeutic strategy for a subset of ccRCC patients. The short-term impact of this study will be to elucidate the impact of manipulation of amino acid metabolism on vulnerability of ccRCC to DDR and DDR inhibitors. We would expect that we could immediately translate this knowledge into clinical application to develop a more effective combination treatment for patients with ccRCC. DDR inhibitors and amino acid deprivation agents have been developed and are currently either approved by the U.S. Food and Drug Administration in other tumor types or in different stages of clinical development. Thus, a successful demonstration of efficacy of combining amino acid deprivation therapy and DDR inhibitors could rapidly progress into a clinical evaluation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010707
Entities
People
- Yi Yin
Organizations
- United States Army
- University of Texas Southwestern Medical Center