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

项目摘要 小细胞肺癌(SCLC)仍然是最致命的肺癌类型，因为肺癌的高转移性 疾病限制了当前治疗药物的疗效和对当前治疗药物的恒定抵抗力。 药物导致了令人沮丧的患者结局。最近靶向信号通路的临床试验包括 在已知与小细胞肺癌相关的分子异常的基础上，mTOR未能产生有希望的靶向 治疗，强调需要明确定义的生物标志物和新的靶向途径。了解关键所在 推动小细胞肺癌发展的代谢改变将为小细胞肺癌预防提供新的策略。 小细胞肺癌细胞与癌前细胞整体基因表达差异的通径分析 表明蛋白质合成途径(EIF4、S6K和mTOR)和其 肿瘤细胞相对癌前细胞的调控途径(EIF2)。该eIF2-ATF4途径通常 减轻代谢压力，然后自我调节，通过促进生存的效应恢复蛋白质合成 包括参与氨基酸代谢的几种酶(BCAT1和ASNS)。然而，这些酶 还没有在代谢应激反应中表现出来。遗传基因的综合分析 异常表明BCAT1和ASNS都是调节肿瘤特异性代谢的潜在因素 改变。虽然这两种酶可能在功能上相关，但亲本U01的资助集中在BCAT1上， 使ASN不具有特征性。因此，为了解决父母赠款的缺口，这项提案旨在确定 使用一种新的小鼠遗传模型和人类小细胞肺癌细胞研究ASNS的作用。ASNS是一种酶，它的 在小细胞肺癌中，表达与蛋白质翻译增加相一致，并可能导致信号的改变 促进肿瘤生长的途径。我们将检验ASN对于SCLC发展是必要的假设 并可抑制肿瘤生长(Aim1)，ASNS在调节eIF2- ATF4代谢应激和促进蛋白质合成的途径有助于小细胞肺癌的进展(目标2)。 这项研究将为推动SCLC增长的机制和新的战略提供关键的见解 小细胞肺癌治疗。该提案的研究部分将辅之以积极的培训计划 这包括提高写作技能的信息性课程，以及学习开发创新想法和 研究工具，积极参与研究交流和研讨会，并积极参与 科学会议。这项研究培训计划，加上我的赞助人和共同导师的支持，将 为我作为一名独立的SCLC研究员的发展提供坚实的基础。

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.