Targeting Branched Chain Amino Acids in Kidney Cancer
Abstract
Kidney cancer is one of the 10 most prevalent malignancies in the world. In 2022, approximately 79,000 new cases and 13,920 deaths due to renal cancer will occur in the United States, with >430,000 new cases diagnosed worldwide. There are multiple subtypes of kidney cancer, each characterized by distinct histological appearances, clinical courses, and therapeutic responses. Clear cell renal cell carcinoma (ccRCC) is the most common, accounting for greater than 75% of all diagnoses. Because of obesity and an aging population, the incidence of ccRCC has steadily risen over the last decade. If ccRCC is detected early and can be surgically resected, 5-year survival rates are relatively favorable compared to many cancers. However, metastatic disease has a catastrophic 5-year survival rate of 10%-12%. At that stage, treatments are sometimes ineffective due to the established resistance of ccRCC to conventional forms of multiple chemotherapies and radiation. Beyond the use of certain cytotoxic drugs, the ccRCC treatment arsenal includes targeted therapies and immunotherapies. Each of these have proven to be somewhat effective, but only in a subset of patients. This lack of consistently effective therapies, particularly in metastatic ccRCC, highlights an urgent need for developing new targets, which could be beneficial to a broader range of ccRCC patients. The overall goal of our proposal is to identify novel treatment strategies that would ultimately benefit most, if not all, ccRCC patients. We have found highly consistent metabolic changes in renal tumors compared to healthy kidney and hope to exploit these with novel approaches. As such, this Kidney Cancer Research Program (KCRP) Idea Development Award application addresses several KCRP Overarching Strategic Goals to (1) increase understanding of kidney cancer biology; (2) develop novel therapeutic strategies for the treatment of kidney cancer; and (3) improve patient care for kidney cancer. The highly innovative aspects of this proposal are its in-depth evaluation of altered branched chain amino acid metabolism typical of ccRCC tumors detected in patients, and revelation of specific enzymes in these pathways as novel druggable targets. We hope to inhibit key metabolic steps in kidney tumors in a way that spares healthy tissue. We propose developing new compounds for ccRCC, and ultimately testing them in individuals with both localized disease and distant metastases in the lung, brain, and bones. Overall, the proposed studies endeavor to rapidly expand treatment options to patients at all stages of disease, especially those that fail other options currently in the clinic.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310859
Entities
People
- Marie Simon
Organizations
- United States Army
- University of Pennsylvania