Exploiting Cholesterol Metabolism to Treat Primary and Metastatic Renal Carcinoma
Abstract
Kidney cancer is one of the ten most prevalent malignancies in the world. In 2018, 63,000 new cases and 15,000 deaths due to renal cancer occurred in the US, with 300,000 new cases diagnosed worldwide. There are multiple subtypes of kidney cancer, each characterized by distinct histological appearences, clinical courses, and therapeutic responses. Clear cell renal cell carcinoma (ccRCC) is the most common, accounting for 85% 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, five-year survival rates are relatively favorable compared to many cancers. However, metastatic disease has a catastrophic 5-year survival rate of <10%. At that stage, treatments are sometimes ineffective due to the established resistance of ccRCC to conventional forms of multiple chemotherapies and radiotherapy. Beyond the use of certain cytotoxic drugs, the ccRCC treatment arsenal includes targeted therapies and immunotherapies. Each of these has 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 therapeutic 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 drug treatments. As such, this KCRP Idea Development Application addresses the Metabolism area of emphasis. The highly innovative aspects of this proposal are its in-depth evaluation of altered cholesterol metabolism typical of ccRCC tumors detected in patients, and revelation of both cholesterol import by a cell surface receptor known as SCARB1, and cellular cholesterol processing by an enzyme called HSD3B7 as new druggable targets. SCARB1 and HSD3B7 are highly abundant in kidney tumors compared to normal kidney and can be inhibited in a way that spares healthy tissue. Most importantly, a drug that inhibits SCARB1 has already been tested in clinical trials for other diseases (e.g., hepatitis), and shown significant safety in humans. We propose repurposing it for ccRCC, and testing it in individuals with both localized disease and distant metastases in the lung, brain, and bones. Future compounds could be identified that inhibit HSD3B7, as a second alternative in ccRCC treatment. 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
- Mar 10, 2021
- Source ID
- W81XWH2010856
Entities
People
- Marie Simon
Organizations
- United States Army
- University of Pennsylvania