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 早期转移、快速生长和缺乏容易靶向的驱动改变。在过去的40年里，SCLC 在临床上主要作为单一疾病进行治疗，使用以铂为基础的联合化疗， 中位生存期仅为10-12个月。必须更好地了解SCLC生物学， 开发新的治疗策略，有效延长患者生存期。SCLC肿瘤扩增或 过表达一个致癌MYC家族成员：MYC、MYCL或MYCN。MYC高SCLC在代谢上 与MYC-低不同，并且具有特定的和可靶向的代谢脆弱性。最有效的治疗 在临床前试验中，治疗MYC-高SCLC的策略是通过聚乙二醇化的 精氨酸脱亚胺酶（ADI-PEG 20）。MYC-高SCLC对ADI-PEG 20特别敏感，因为它们缺乏 精氨酸琥珀酸合成酶1（ASS 1），催化尿素从头合成精氨酸 周期尽管如此，SCLC肿瘤最终发展出对ADI-PEG 20（ABIG）的耐药性，这与RE-PEG 20的耐药性相对应。 ASS 1的表达。在Ablation后，肿瘤获得次级代谢依赖性，其可以靶向于 延长ADI-PEG 20反应和患者生存期。初步数据显示，ARAM-SCLC依赖于丝氨酸 和一碳（1C）代谢，这可以用抗叶酸剂靶向。初步数据还显示， 候选转录调节因子可能控制SCLC中的ApoA。转录激活因子4（ATF 4），a 应激反应转录因子，是一个预测的基因程序的上游调控富集在拟南芥中 与初始SCLC相比-通过批量和单细胞RNA测序确定。急性精氨酸诱导ATF 4 在小细胞肺癌中的剥夺，并继续表达与其靶基因在Ablation。申请人将 采用SCLC对ADI-PEG 20的反应的单细胞RNA-seq衍生模型，体内代谢物谱分析 同位素示踪和基于CRISPR的基因编辑来询问ATF 4是否控制Ablation。假设为 这项研究是ATF 4通过以ASS 1依赖的方式增强丝氨酸和1C代谢来驱动Ablation。 实验将在两个特定的目的进行，以测试ATF 4是否支配：1）MYC-高的敏感性 SCLC对ADI-PEG 20的敏感性，和/或2）ABI-SCLC对IC代谢抑制剂的敏感性。收集的知识 这项研究将为改善ADI-PEG 20疗效的联合治疗策略提供信息， 延长SCLC和其他低ASS 1肿瘤患者的生存期。这项研究将提供独特的 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大目标。拟议的研究将发生 在亨斯迈癌症研究所和犹他州大学进行了三年多的培训， 资源丰富的培训环境，在特鲁迪奥利弗博士的实验室。