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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

基本信息

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
项目类别：
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

项目摘要

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