Significance to VA : Metabolic remodeling is integral to cancer biology. The discovery of somatic mutations in genes encoding metabolic enzymes provided insights into how subverting metabolism promotes cancer. These studies also uncovered opportunities for metabolic interventions with anti-cancer activity. Building on this idea, we postulated that the intermediate metabolite alpha-ketoglutarate (αKG) could suppress tumor growth. We tested this concept in a large panel of lymphomas (cell lines and primary tumors), in vitro and in vivo, and found that αKG significantly inhibited lymphoma cell growth, induced apoptosis, and decreased tumor burden/improved survival of mice harboring lymphomas. Testing new, more effective and less toxic treatment strategies for lymphoma is particularly important for Veterans, and the VHA, because lymphoma is a cancer type uncontrovertibly associated with military service. The increased risk for lymphoma development is firmly linked to exposure to agent orange and lymphoma is a presumptive condition in veterans of recent campaigns who may have been exposed to environmental toxins in the theater of operations. Innovation and impact : We found that αKG suppresses lymphoma growth by promoting amino acid depletion. This finding unveiled an innovative way to “starve” cancer cells, a long-sought goal in cancer therapeutics. Further, we also found that treatment with αKG uncovers multiple additional cancer vulnerabilities, which can be targeted with existing, clinical grade, small- molecule inhibitors. Thus, this project may have a significant impact in the treatment and cure rate of lymphomas and related cancers. Specific aims : Aim 1. Characterize αKG’s impact on BCAT activity/flux direction, leucine depletion and MTORC1 inhibition. Hypothesis: αKG imposes the flux of BCAT reactions towards the conversion of BCAA into BCKA, and the attendant leucine depletion inhibits MTORC1 via Sestrin2-GATOR-Rag2 interactions. Aim 2. Examine the role of GOT