Targeting Mitochondrial Defects in Kidney Cancer
Abstract
The overarching focus of this study is to identify more effective therapies that will improve the overall survival of kidney cancer patients. Currently, kidney cancer patients presenting with more rare non-clear cell renal cell carcinoma (RCC) tumor subtypes such as chromophobe or papillary RCC variants have limited treatment options and poor outcomes. This is, in part, due to the diverse genetic, molecular, and metabolic landscape of these tumors. Improving the molecular and metabolic characterization of non-clear cell RCC variants holds promise to lead to more appropriate clinical management and development of more effective forms of therapy. We have focused our research on understanding the role of mitochondrial dysfunction and how it serves as a metabolic driver of non-clear cell RCC tumors. The overarching goal of this work is to characterize the metabolic dependencies in these tumors so that we may therapeutically target the metabolic pathways required to keep the tumor(s) alive. Therefore, we sought to identify effective new treatment strategies that target and inhibit nutrient consumption in aggressive tumors. Fast-growing tumors require excessive nutrients to support tumor cell metabolism and growth. Importantly, the restriction of key metabolic pathways causes an energy crisis that results in tumor cell death. Simply put, if a tumor cannot eat it cannot survive. This approach represents a paradigm shift in the treatment of cancer as we move toward developing personalized therapeutic strategies that selectively target the metabolic needs unique to each tumor as a novel means to overcome therapy resistance. This strategy has proved highly effective for squamous cell tumors, a particularly aggressive and metabolically active type of tumor that has a voracious appetite for sugar and amino acids, which are the building blocks of protein. By restricting specific nutrients such as sugar and the amino acid glutamine we are able to selectively kill highly aggressive tumors while preserving the normal healthy surrounding tissue. Using imaging and molecular analysis we are able to profile the nutrient requirements of metabolically active tumors and tailor precise therapies to inhibit tumor cell metabolism and growth. Importantly, we have identified that metabolically active non-clear cell RCC tumors that share the same metabolic signatures identified in squamous tumors. We predict that metabolically active therapy-resistant kidney cancer across a broad set of tumor types can be successfully treated by inhibiting sugar and amino acid metabolism and will be the focus of our proposed study. Our work holds the promise of much needed advancements across this disease spectrum.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210944
Entities
People
- David B Shackelford
Organizations
- United States Army
- University of California, Los Angeles