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

靶向 BCAT1 和支链氨基酸代谢用于检测和预防 SCLC

• 批准号: 10380321
• 负责人: Kwon-Sik Park
• 金额: $ 8.21万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380321
• 关键词: Address; Affect; Applications Grants; Automobile Driving; Biological Markers; Branched-Chain Amino Acids; Cessation of life; Clinical Trials; Communication Research; Detection; Development; Disease; Enzymes; Eukaryotic Initiation Factor-2; FRAP1 gene; Foundations; Genes; Grant; Growth; Human; Learning; Malignant neoplasm of lung; Mentors; Metabolic; Metabolic Pathway; Metabolic stress; Molecular; Molecular Abnormality; Mutate; Nature; Parents; Pathway Analysis; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Premalignant Cell; Prevention; Protein Biosynthesis; Proteins; Regulatory Pathway; Research; Research Personnel; Research Training; Resistance; Role; Signal Pathway; Solid; Testing; Therapeutic Agents; Training; Translations; Woman; Writing; amino acid metabolism; biological adaptation to stress; cancer therapy; genetic analysis; improved; innovation; insight; lung cancer cell; lung cancer prevention; lung small cell carcinoma; men; mouse model; neoplastic cell; novel; novel strategies; novel therapeutic intervention; parent grant; skills; symposium; targeted treatment; tool; transcriptome; tumor; tumor growth; tumor progression

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.

项目摘要 小细胞肺癌（SCLC）仍然是最致命的肺癌类型，因为其高转移性。 疾病限制了当前治疗剂的功效和对当前治疗剂的恒定抗性 药物会导致患者的不良结局。最近针对信号通路的临床试验，包括 基于已知的与SCLC相关的分子异常，mTOR未能产生有希望的靶向治疗。 治疗，强调需要明确的生物标志物和新的靶向途径。了解关键 促进SCLC发展的代谢改变将为SCLC预防提供新的策略。 我们对SCLC细胞和癌前细胞之间整体基因表达差异的通路分析 表明蛋白质合成途径（EIF 4、S6 K和mTOR）及其 调节途径（EIF 2）在肿瘤细胞相对于癌前细胞。这种EIF 2-ATF 4途径通常 减轻代谢应激，然后通过促生存效应子调节自身以恢复蛋白质合成 包括参与氨基酸代谢的几种酶（BCAT 1和ASNS）。然而，这些酶 还没有在代谢应激反应中得到表征。遗传学综合分析 BCAT 1和ASNS都是调节肿瘤特异性代谢的潜在因子， 变化虽然这两种酶可能在功能上相关，但母公司U 01资助的重点是BCAT 1， 留下未表征的ASNS。因此，为了解决父母补助金的差距，本提案旨在确定 ASNS的作用使用一种新的遗传小鼠模型和人SCLC细胞。ASNS是一种酶 表达与SCLC中增加的蛋白质翻译一致，可能有助于信号转导的改变。 促进肿瘤生长的途径。我们将检验ASNS对小细胞肺癌的发展是必要的这一假设 并且可以被抑制以减缓肿瘤生长（Aim 1），并且ASNS在调节EIF 2- 代谢应激和促进蛋白质合成的ATF 4途径有助于SCLC进展（目的2）。 这项研究将为SCLC生长的驱动机制和新的策略提供重要的见解， SCLC治疗这项建议的研究部分将辅之以一项积极的培训计划 这包括提高写作技能和学习发展创新思想的信息课程， 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，加上我的赞助商和共同导师的支持，将 提供了一个坚实的基础，以促进我作为一个独立的SCLC研究人员的发展。