BLRD Merit Review Research Career Scientist (RCS) Award (IK6)

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Project Summary/Abstract The goals of my research programs are to elucidate molecular mechanisms of tumor angiogenesis, cancer metabolism, and anti-tumor immunity, and to translate our discoveries towards improved cancer therapy. During this RCS award period I will continue to: (1) Targeting mTOR signaling pathways in lung cancer subtypes that are refractory to current targeted therapies. We demonstrated previously that mTOR is a common signaling node downstream of “bypass” kinases, and targeting mTOR represents a promising approach in multiple settings of drug resistance. Rictor, a unique components of mTORC2, is commonly amplified in approximately 13% of lung cancer. While mTOR kinase inhibitors inhibit both mTORC1 and mTORC2, selective inhibition of mTORC2 has the advantage of not perturbing the mTORC1-dependent negative feedback loops and mTORC1- mediated inhibition of macropinocytosis in mutant Ras tumors. We found that point mutations disrupting mLST8-mTOR binding specifically destabilize mTORC2 without affecting mTORC1, pointing to a viable strategy for inhibitor design. We will continue to gain a rigorous understanding of the contribution of mTORC2 to subtypes of lung cancer that are currently refractory to targeted therapies, and to further investigate if targeting mLST8 can be used to selectively inhibit mTORC2. (2) Determine the therapeutic potential of low dose mTORC1 inhibitors in normalizing tumor blood vessels and recruiting anti-tumor lymphocytes. My lab pioneered studies of mTORC1 and mTORC2 in tumor blood vessels. We discovered that lymphocyte infiltration increased significantly in the tumors with endothelial-specific deletion of Raptor (mTORC1 inactivation). Although standard high doses of Rapalogs can inhibit immune function, we discovered that a low, relatively immune- sparing dose of everolimus (RAD001), an mTORC1 inhibitor, normalized tumor blood vessels and enhanced tumor infiltrating lymphocytes. Promising results of pre-clinical animal studies will set the stage for initiating a clinical trial to improve immunotherapy. (3) Role of EphA2 RTK in glutamine metabolism and anti-tumor immunity. Our serendipitous discovery that the ephrin-A1/EphA2 signaling axis regulates lipid accumulation in cancer cells has led us systematically to investigate the role of ephrin-A1/EphA2 in tumor metabolism. Global metabolic profiling revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis, in ephrin-A1 knockout or EphA2 overexpressing tumor cells. Investigation of mechanisms led us to discover that EphA2 RTK promotes glutamine metabolism by upregulation of the glutamine transporter ASCT2 (encoded by SLC1A5) and glutaminase GLS via activation of the transcription coactivators YAP and TAZ. Knockout of GLS in tumor cells, however, increases anti-tumor immunity. We will continue to dissect the effects and mechanisms by which tumor cell-specific loss of GLS on immune cells. Further, we will test and compare inhibitors of glutamine access (V-9302) or glutaminase (CB-839) on their effects in inhibiting tumor cells versus anti-tumor lymphocytes. Significance: Success of these projects will have significant translational potential for the veteran populations, by identifying new therapeutic targets for lung cancer subtypes that are refractory to current targeted therapies, and by enhancing immunotherapies via normalization of tumor blood vessels and inhibition of tumor metabolism.