The high mortality of small cell lung cancer (SCLC) is largely due to its invariable resistance to current cytotoxic therapies. Chemoprevention has been considered as an alternative to existing therapeutics on the basis of long tumor latency and the well-defined high-risk population (e.g. smokers). Identification of tractable targets for prevention and early detection requires an understanding of molecular changes underlying early- stage tumor development. We found that enhanced ribosome biogenesis and protein synthesis are critical for MYC family-driven transformation of precancerous precursors (preSC) into fully tumorigenic cells. Both human and mouse SCLC cells are extremely sensitive to a specific inhibitor of ribosome biogenesis that has also been shown to reduce tumor growth in a genetically engineered mouse model. Analysis of the MYC-driven oncogenic gene signature revealed branched-chain aminotransferase 1 (BCAT1) as a potential modulator of both metabolic adaptation and related stress response to promote cellular homeostasis. BCAT1 is an enzyme that catalyzes transfer of the ?-amino nitrogen from branched-chain amino acids (BCAAs including leucine) to ?-ketoglutarate to produce branched-chain ?-keto acids (BCKAs) and glutamate. This enzyme routes BCAAs into multiple metabolite pools for biosynthesis and regulates levels of BCAAs, specifically leucine, that stimulate protein synthesis by acting as indicators of nutrient availability. BCAT1 has recently been implicated in multiple types of cancers, including glioblastoma and mouse Kras/p53-driven lung adenocarcinoma. In this application, we will test the hypotheses that enhanced BCAT1 promotes SCLC development by controlling protein synthesis and stress response, and that altered levels of BCAA metabolites inform early BCAT1- dependent SCLC development. To test these hypotheses, we propose the following Aims.
Aim 1 : To determine the necessity of BCAT1 for SCLC development, we will evaluate the tumor suppressive effects of knocking out Bcat1 and examine the effects of pharmacological inhibition of BCAT1 on SCLC development and long-term survival in vivo.
Aim 2 : To determine the role of BCAT1 in protein synthesis and stress response during SCLC development, we will manipulate BCAT1 and determine the resulting impact on biochemical interactions among related proteins and pathways that influence proliferation and survival of L-Myc-induced transforming cells, a model of early stage SCLC. We will also determine the significance of BCAA metabolism in tumor development in vivo by setting up variable conditions that mimic different outcomes of the metabolic reaction using a BCAA-defined diet.
Aim 3 : To test alterations in BCAA metabolites as biomarkers for BCAT1- dependent SCLC development, we will monitor changes in plasma BCAA and BCKA levels during SCLC development in vivo and examine the clinical correlation of plasma levels of these metabolites with a SCLC diagnosis. The expected outcome of this proposal will provide critical insights into novel strategies for targeted prevention using minimally invasive detection methods and intervention using low-toxicity drugs or nutrition.
Small cell lung cancer (SCLC) is the most aggressive form of lung cancers that affects both men and women and cause deaths of approximately 30,000 patients in the United States and 200,000 patients worldwide each year. Late diagnosis of SCLC often limits treatment options to cytotoxic chemotherapies, which have remained largely unchanged for the past 30 years and failed to significantly improve patient outcomes. The decades-long latency of SCLC and well-defined high-risk population (chronic and former heavy smokers) support the potential viability of prevention strategies. Therefore, novel means for early detection and prevention will significantly improve overall clinical outcomes. We propose to characterize specific molecular changes during early stage SCLC development and assess them as potential biomarkers for early detection and prevention of this devastating disease.
