Project Summary/Abstract This proposal describes a five-year training program to launch a research career in a novel niche at the intersection between endocrinology and cancer biology. The candidate is an endocrinology fellow at Weill Cornell Medical Center, who has been training to become a physician-scientist for over ten years. The proposed research will be carried out under the mentorship of Lewis C. Cantley, PhD, a leader in the field of cancer biology and biochemistry who has trained numerous young investigators. An advisory committee of talented scientists has also been assembled to offer guidance in career development and experimentation. The research environment provides extensive resources, core facilities, and intellectual expertise. Therefore, it is an ideal training setting in which to develop the requisite skills to become an independent physician-scientist. Participation in didactic courses and professional development seminars will enhance the educational success of the program. The cancer anorexia-cachexia syndrome (CACS) is a systemic metabolic disorder characterized by the catabolism of nutrient-rich tissues, such as muscle and adipose tissue. Patients with CACS have reduced mobility, worsened quality of life, and shortened survival. Therapeutic strategies to limit muscle loss are predicted to reverse these deleterious outcomes, independent of direct cancer treatment. CACS has no effective treatment or known etiology, in part, because animal models poorly mimic the findings in patients. However, in preliminary experiments using an inducible, genetically engineered mouse model of non-small cell lung cancer (NSCLC), the applicant has identified and characterized a model that reliably replicates CACS in humans. These mice display a unique metabolic profile, characterized by the loss of PPARα-dependent ketone production by the liver and a rise in endogenous glucocorticoid levels. Restoring ketone production using the PPARα agonist, fenofibrate, reduces glucocorticoids and prevents the loss of skeletal muscle mass and body weight. This proposal expands upon the preliminary experiments and seeks to clarify the causal relationship between the observed changes in systemic metabolism and skeletal muscle loss in NSCLC-associated CACS. The proposed aims are to test the hypothesis that skeletal muscle degradation results from the loss of ketone production (Aim 1) or the subsequent rise in glucocorticoids (Aim 2). Additionally, this proposal will seek to identify the tumor-released factor that initiates the reduction in hepatic PPARα expression in CACS mice (Aim 3). These experiments will elucidate the systemic metabolic signals driving muscle loss in an animal model of NSCLC that accurately mimics the observed clinical syndrome. The expectations are to identify specific tumor- secreted proteins that reduce hepatic ketone production, and demonstrate that ketone replacement therapy is a useful therapeutic strategy. These results will not onl...