Therapeutically Targeting Mitochondria Bioenergetics in Immune-Cold Non-Small Cell Lung Cancer
Abstract
The overarching focus of this study is to identify more effective therapies that will improve the overall survival of lung cancer patients. Recent breakthroughs with immune based therapies are now able to induce durable responses in approximately 20-30% of lung cancer patients. Unfortunately, many patients with tumor mutations in the KRAS, LKB1, and EGFR genes have “immune cold” lung tumors that are resistance to immune-based therapies. The majority of these patients who do not qualify for immune therapy will receive chemotherapy or a tyrosine kinase inhibitor, with most patients developing resistance to treatment. Therefore, we sought to identify a new approach, one that inhibits nutrient consumption in aggressive metabolically active lung tumors. Fast-growing tumors require excessive nutrients to support tumor cell metabolism and growth. Importantly, the restriction of key metabolic pathways causes “energetic 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 improve treatment outcomes. This strategy has proved effective in preclinical studies of KRAS, LKB1, and EGFR mutant lung tumors, which have a voracious appetite for sugar and other nutrients. By restricting specific nutrients such as sugar, we are able to selectively kill highly aggressive lung tumors while preserving the normal healthy surrounding tissue. A major requirement of metabolic-based targeted therapies is to have the metabolic needs of the tumor mapped out. Using imaging and molecular analysis, we are able to profile and map the nutrient requirements of metabolically active tumors. This enables us to tailor precise therapies to inhibit tumor cell metabolism and growth that we anticipate will serve as effective second line treatment options for patients. In this study, we will examine in depth the metabolic needs of KRAS, LKB1, and EGFR mutant lung cancer in order to identify and translate effective metabolic therapies into clinical use.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010439
Entities
People
- David B Shackelford
Organizations
- United States Army
- University of California, Los Angeles