Investigating and targeting metabolic vulnerabilities of MYC-driven small cell lung cancer

研究和靶向 MYC 驱动的小细胞肺癌的代谢脆弱性

• 批准号: 10748278
• 负责人: ABBIE SHAYE IRELAND
• 金额: $ 4.77万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748278
• 关键词: ASCL1 gene; Acute; Anabolism; Arginine; Arginine deiminase; Aspartate; BETA2 protein; Cancer Biology; Cancer Model; Carbon; ChIP-seq; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Computer Analysis; Consumption; Data; Data Analyses; Data Set; Dependence; Development; Disease; Disease model; Environment; Enzymes; Family member; Folic Acid Antagonists; Genes; Genetic Transcription; Genetically Engineered Mouse; Glean; Goals; Health; Human; Huntsman Cancer Institute at the University of Utah; In Vitro; Isotopes; Knowledge; Lung Neuroendocrine Neoplasm; MYCL1 gene; MYCN gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolism; Mission; Modeling; Neoplasm Metastasis; Neuroendocrine Tumors; Nucleotide Biosynthesis; Oncogenic; Patients; Pharmaceutical Preparations; Physiological; Platinum; Play; Process; Regulator Genes; Research; Resistance; Resistance development; Resources; Role; Secondary to; Serine; Specific qualifier value; Starvation; Stress; System; Testing; Therapeutic; Time; Training; United States National Institutes of Health; activating transcription factor; activating transcription factor 4; argininosuccinate synthase; base editing; cancer subtypes; chemotherapy; chromatin immunoprecipitation; deprivation; desensitization; effective therapy; experimental study; gene synthesis; human model; improved; in vivo; inhibitor; lung cancer cell; metabolomics; molecular subtypes; mouse model; novel; nucleotide metabolism; overexpression; preclinical study; preclinical trial; prevent; programs; rapid growth; resistance mechanism; response; single-cell RNA sequencing; small cell lung carcinoma; standard of care; targeted treatment; therapeutically effective; therapy resistant; transcription factor; transcriptomics; treatment strategy; tumor; tumor metabolism; urea cycle

PROJECT ABSTRACT Small cell lung cancer (SCLC) is a fatal neuroendocrine lung tumor that is challenging to treat due to early metastasis, rapid growth, and a lack of easily targetable driver alterations. For the last ~40 years, SCLC has been treated primarily as a single disease in the clinic with combination, platinum-based chemotherapy that offers a median survival of only ~10-12 months. It is imperative to better understand SCLC biology to enable development of novel treatment strategies that effectively prolong patient survival. SCLC tumors amplify or overexpress one oncogenic MYC family member: MYC, MYCL, or MYCN. MYC-high SCLCs are metabolically distinct from MYC-low, and have specific and targetable metabolic vulnerabilities. The most effective therapeutic strategy for treatment of MYC-high SCLCs in preclinical trials is deprivation of circulating arginine by pegylated arginine deiminase (ADI-PEG20). MYC-high SCLCs are particularly sensitive to ADI-PEG20, because they lack the enzyme argininosuccinate synthetase 1 (ASS1) that catalyzes de novo synthesis of arginine by the urea cycle. Still, SCLC tumors eventually develop resistance to ADI-PEG20 (ADIR) that corresponds with re- expression of ASS1. Upon ADIR, tumors acquire secondary metabolic dependencies that may be targeted to prolong ADI-PEG20 response and patient survival. Preliminary data show that ADIR SCLC depends on serine and one-carbon (1C) metabolism, which can be targeted with anti-folates. Preliminary data also delineate candidate transcriptional regulators that may govern ADIR in SCLC. Activating transcription factor 4 (ATF4), a stress-responsive transcription factor, is one predicted upstream regulator of gene programs enriched in ADIR vs naïve SCLCs—determined by bulk and single-cell RNA sequencing. ATF4 is induced upon acute arginine deprivation in SCLC and continues to be expressed with its target genes during ADIR. Here, the applicant will employ a single-cell RNA-seq-derived model of SCLC response to ADI-PEG20, metabolite profiling, in vivo isotope tracing, and CRISPR-based gene editing to interrogate whether ATF4 governs ADIR. The hypothesis for this research is that ATF4 drives ADIR by enhancing serine and 1C metabolism in an ASS1-dependent manner. Experiments will be performed in two specific aims to test whether ATF4 governs: 1) the sensitivity of MYC-high SCLCs to ADI-PEG20, and/or 2) the sensitivity of ADIR SCLCs to 1C metabolism inhibitors. Knowledge gleaned from this research will inform combination treatment strategies that improve the efficacy of ADI-PEG20 and extend survival of patients with SCLC and other ASS1-low tumors. The proposed research will provide unique opportunities for the applicant to gain expertise in cancer biology, cancer metabolism, and computational analysis of -omics data—three major goals of the applicant’s training plan. The proposed research will occur over three years of training at Huntsman Cancer Institute and the University of Utah, a collaborative and resource-rich training environment, in the lab of Dr. Trudy Oliver.

项目摘要 小细胞肺癌（SCLC）是一种致命的神经内分泌肺肿瘤，由于以下原因治疗起来具有挑战性 早期转移、快速生长以及缺乏易于靶向的驱动改变。在过去约 40 年里，SCLC 在临床上主要将其作为单一疾病进行治疗，采用基于铂类的联合化疗， 中位生存期仅为约 10-12 个月。必须更好地了解 SCLC 生物学，以实现 开发新的治疗策略，有效延长患者的生存期。 SCLC 肿瘤扩增或 过度表达一种致癌 MYC 家族成员：MYC、MYCL 或 MYCN。 MYC 高的 SCLC 具有代谢性 与 MYC-low 不同，并且具有特定的、可针对的代谢脆弱性。最有效的治疗方法 临床前试验中治疗高 MYC SCLC 的策略是通过聚乙二醇化剥夺循环精氨酸 精氨酸脱亚胺酶（ADI-PEG20）。 MYC 高的 SCLC 对 ADI-PEG20 特别敏感，因为它们缺乏 精氨酸琥珀酸合成酶 1 (ASS1)，催化尿素从头合成精氨酸 循环。尽管如此，SCLC 肿瘤最终会对 ADI-PEG20 (ADIR) 产生耐药性，这与重新 ASS1 的表达。 ADIR 后，肿瘤获得次级代谢依赖性，可能针对 延长 ADI-PEG20 反应和患者生存期。初步数据表明 ADIR SCLC 依赖于丝氨酸 和一碳（1C）代谢，可以用抗叶酸药物来靶向。初步数据也描绘了 可能控制 SCLC 中 ADIR 的候选转录调节因子。激活转录因子 4 (ATF4) 应激反应转录因子，是一种预测的富含 ADIR 的基因程序上游调节因子 与初始 SCLC——通过批量和单细胞 RNA 测序确定。 ATF4 由急性精氨酸诱导 SCLC 中的剥夺并在 ADIR 期间继续与其靶基因一起表达。在此，申请人将 采用单细胞 RNA-seq 衍生的 SCLC 对 ADI-PEG20 反应的模型，体内代谢物分析 同位素追踪和基于 CRISPR 的基因编辑来询问 ATF4 是否控制 ADIR。假设为 这项研究表明，ATF4 通过以 ASS1 依赖性方式增强丝氨酸和 1C 代谢来驱动 ADIR。 实验将针对两个特定目标进行，以测试 ATF4 是否具有控制作用：1）MYC-high 的敏感性 SCLC 对 ADI-PEG20 的敏感性，和/或 2) ADIR SCLC 对 1C 代谢抑制剂的敏感性。收集到的知识 这项研究将为联合治疗策略提供信息，以提高 ADI-PEG20 的疗效和 延长 SCLC 和其他 ASS1 低肿瘤患者的生存期。拟议的研究将提供独特的 申请人有机会获得癌症生物学、癌症代谢和计算方面的专业知识 组学数据分析——申请人培训计划的三个主要目标。拟议的研究将发生 在亨茨曼癌症研究所和犹他大学接受了三年多的培训，这是一个合作和 资源丰富的培训环境，在Trudy Oliver博士的实验室。