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，由于治疗而挑战 早期转移，快速增长以及缺乏易于靶向的驾驶员改变。在过去的40年中，SCLC 在诊所中，主要被视为单一疾病，结合了铂类化学疗法， 中位生存期仅约10-12个月。必须更好地了解SCLC生物学以启用 开发有效延长患者生存的新型治疗策略。 SCLC肿瘤放大或 过表达一个致癌的MYC家庭成员：MYC，MYCL或MYCN。 Myc-High SCLC是代谢的 与MYC-LOW不同，并且具有特定且可定位的代谢脆弱性。最有效的疗法 在临床前试验中治疗MYC-HIGH SCLC的策略是剥夺循环精氨酸 精氨酸脱节酶（ADI-PEG20）。 Myc-High SCLC对ADI-PEG20特别敏感，因为它们缺乏 精氨酸偶联酶合成酶1（ASS1），尿素催化精氨酸的从头合成 循环。尽管如此，SCLC肿瘤最终会产生对ADI-PEG20（ADIR）的抗性 Ass1的表达。在ADIR时，肿瘤获得了可能针对的次级代谢依赖性 延长ADI-PEG20反应和患者生存。初步数据显示，Adir SCLC取决于串行 和一碳（1C）代谢，可以用抗粉状靶向。初步数据也描述 可以在SCLC中管理ADIR的候选抄本监管机构。激活转录因子4（ATF4），A 应力响应性转录因子是富含ADIR的基因程序的预测上游调节因子 与幼稚的sclcs - 通过散装和单细胞RNA测序确定。急性精氨酸诱导ATF4 SCLC中的剥夺，并在ADIR期间继续用其靶基因表达。在这里，适用的将 员工对ADI-PEG20，代谢物分析，体内的SCLC响应的单细胞RNA-seq衍生模型 同位素跟踪和基于CRISPR的基因编辑，以询问ATF4是否控制ADIR。假设 这项研究是，ATF4通过以ASS1依赖性方式增强串行和1C代谢来驱动ADIR。 实验将以两个特定目的进行测试，以测试ATF4是否控制：1）MYC-HIGH的灵敏度 SCLC至ADI-PEG20和/或2）ADIR SCLC对1C代谢抑制剂的敏感性。知识清理了 这项研究将为提高ADI-PEG20和 扩展SCLC和其他ASS1-低肿瘤患者的存活率。拟议的研究将提供独特的 申请人获得癌症生物学，癌症代谢和计算方面的专业知识的机会 分析-omics数据 - 申请人培训计划的三个主要目标。拟议的研究将发生 在亨斯曼癌症研究所和犹他大学进行了三年多的培训， 在Trudy Oliver博士的实验室里，资源丰富的培训环境。