Targeting BCAT1 and branched-chain amino acid metabolism for the detection and prevention of SCLC

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Project Abstract Small cell lung cancer (SCLC) remains the deadliest type of lung cancer as the highly metastatic nature of the disease limits the efficacy of current therapeutic agents and the invariable resistance to current therapeutic agents contributes to the dismal patient outcome. Recent clinical trials of targeting signaling pathways, including mTOR, on the basis of known molecular abnormalities associated with SCLC failed to yield a promising targeted therapy, underscoring the need for well-defined biomarkers and novel target pathways. Understanding the key metabolic alterations that drive SCLC development will provide insight into novel strategies for SCLC prevention. Our pathway analysis of the global gene expression differences between SCLC cells and precancerous cells indicates the significant enrichment of both the protein synthesis pathway (EIF4, S6K, and mTOR) and its regulatory pathway (EIF2) in the tumor cells relative to precancerous cells. This EIF2-ATF4 pathway generally mitigates the metabolic stress and then regulates itself to restore protein synthesis via pro-survival effectors including several enzymes involved in amino acid metabolism (BCAT1 and ASNS). However, these enzymes have not been characterized in the metabolic stress response. The integrated analysis of the genetic abnormalities points to both BCAT1 and ASNS as potential factors that regulate the tumor specific metabolic changes. While these two enzymes may be functionally related, the parent U01 grant is focused on BCAT1, leaving ASNS uncharacterized. Therefore, to address the gap in the parent grant, this proposal aims to determine the role of ASNS using a novel genetically mouse model and human SCLC cells. ASNS is an enzyme whose expression coincides with increased protein translation in SCLC and may contribute to alterations in signaling pathways that promote tumor growth. We will test the hypotheses that ASNS is necessary for SCLC development and can be inhibited to slow tumor growth (Aim1), and that ASNS plays a crucial role in regulating the EIF2- ATF4 pathway of metabolic stress and facilitating protein synthesis to contribute to SCLC progression (Aim 2). This research will provide critical insights into the mechanisms driving SCLC growth and novel strategies for SCLC treatments. The research component of this proposal will be supplemented with an active training plan that includes informative coursework for improving writing skills and learning to develop innovative ideas and research tools, active participation in research communications and seminars, and active participation in scientific conferences. This research training plan, together with the support of my sponsor and co-mentor, will provide a solid foundation to promote my development as an independent SCLC researcher.