Metabolic Modulation Suppresses Survival Signals in B-Cell Lymphoma

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 GOT1/GOT2 on the αKG-mediated aspartate depletion. Hypothesis: αKG drives GOT1/2 flux towards generation of glutamate, impeding the reverse reaction, and thus blocking glutamine anaplerosis, an essential process for the growth of tumor cells. We postulate that these metabolic perturbations will make lymphomas over reliant on glucose for energy and biomass production. Aim 3. Test in vitro and in vivo the anti-lymphoma activity of metabolic centered small molecule inhibitors as single agents or in combination with αKG. Hypothesis: αKG’s modulation of transaminase reactions creates metabolic vulnerabilities that can be exploited therapeutically. We predict that clinical grade inhibitors of BCKDK, by promoting the irreversible conversion of BCKA into branched chain acyl-CoAs will display anti-lymphoma activity as single agent and be synergistic with αKG. Likewise, αKG-driven leucine depletion may improve the anti-lymphoma activity of mTOR inhibitors. In addition, αKG’s block of glutamine anaplerosis will render lymphomas uniquely sensitive to glucose transporters (GLUT) inhibitors. : In this project, we will use of genetic models of human lymphomas (cell lines and primary tumors) with knockout, or ectopic expression, of enzymes that control amino acid catabolism, transport, and MTORC1 subcellular localization and activity. These models will be extensively examined with mass spectrometry-based isotope labeled flux analysis and utilized in vitro and in vivo to test the anti-lymphoma effect of the novel Methodology metabolic-centered combinations of αKG with BCKDK, MTOR and GLUT inhibitors. Path to translation : Various formulations of αKG have been shown to be safe in humans, and the small molecule inhibitors to be tested are clinical grade or FDA-approved. We have a track record of concrete clinical translation in the field of lymphoma, and we are confident that if αKG’s anti-lymphoma efficacy is confirmed in this study we will be in an excellent position to expeditiously b Project Number: 1I01RD001059-01 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Ricardo Aguiar | Institution: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM, SAN ANTONIO, TX | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 HEMA-G (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11297406