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Mechanisms of Arginine Deprivation in Small Cell Lung Cancer

小细胞肺癌中精氨酸剥夺的机制

基本信息

批准号：
10642432
负责人：
Trudy Gale Oliver
金额：
$ 38.19万
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：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642432
关键词：
ASCL1 gene ATAC-seq Address Amino Acids Anabolism Arginine Arginine deiminase Autophagocytosis BETA2 protein Biological Markers Blood Circulation Cancer Patient Carbon Cell Death Cell Line Cells Cessation of life Chemotherapy-Oncologic Procedure Chloroquine Clinical Trials Congresses Data Disease Disease model Drug Combinations Environment Enzymes Extensive Stage FRAP1 gene Family Family member Ferritin Genetic Genetically Engineered Mouse Human Human Cell Line Immune system Immunocompetent Immunotherapy Ireland Knock-out Lead Light Lung Neuroendocrine Neoplasm MYCL1 gene Malignant Neoplasms Malignant neoplasm of lung Mesenchymal Metabolic Metabolic Pathway Metabolism Mission Mus NCOA4 gene Pathway interactions Patients Pharmaceutical Preparations Pharmacology Polyamines Population Public Health Quality of life Relapse Research Resistance Resistance development Role Signal Transduction Solid Neoplasm Starvation Survival Rate TP53 gene Technology Testing Therapeutic Time United States National Institutes of Health Work argininosuccinate synthase cancer cell cancer subtypes cancer therapy cancer type chemotherapy deprivation design erastin human disease improved in vivo innovation lung cancer cell lung small cell carcinoma molecular phenotype molecular subtypes mortality neoplastic cell new therapeutic target novel patient derived xenograft model patient stratification resistance mechanism response single-cell RNA sequencing standard of care targeted treatment transcription factor transcriptome sequencing treatment strategy tumor

项目摘要

Project Summary Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung tumor responsible for over 30,000 deaths each year in the US. SCLC has a two-year survival rate of ~6% with no approved targeted therapies beyond the recent approval of immunotherapy. SCLC is initially highly responsive to chemotherapy, but rapidly develops resistance leading to mortality in ~12 months. A major unmet need for SCLC treatment is the identification of new therapeutic targets and treatment strategies. SCLC has historically been treated as a single disease without patient stratification. SCLC is driven by distinct MYC family members (MYCL or MYC), which are notoriously difficult to drug. We and others showed that MYC and MYCL-driven SCLC have distinct molecular phenotypes with unique vulnerabilities to targeted therapies. We performed unbiased metabolite profiling on MYC versus MYCL-driven subtypes of SCLC and found that they are metabolically distinct. Using human cell lines, genetically-engineered mouse models (GEMMs), and human patient-derived xenografts (PDX), we found that MYC-driven SCLC is uniquely dependent on the amino acid arginine. Arginine depletion with pegylated arginine deiminase (ADI-PEG20) is the most effective drug we have tested in >25 drug combinations in GEMMs. Consistently, MYC-driven SCLC has reduced ASS1 expression, the enzyme required to synthesize arginine. In preliminary data, we discovered that MYC-driven tumor cells treated with ADI-PEG20 undergo autophagy and ferroptosis. After dramatic initial responses, tumors eventually relapse with re-expression of ASS1 and metabolic reprogramming with changes in one-carbon, polyamine, and ferroptosis-related pathways. We hypothesize that arginine deprivation in MYC-driven SCLC promotes autophagy and death by ferroptosis, and that inhibition of ferroptosis will improve the efficacy of ADI-PEG20. We also hypothesize that during ADI-PEG20 resistance, re- expression of ASS1 leads to metabolic reprogramming that can be blocked by targeting new metabolic pathways. To test these hypotheses, our objectives are: 1) Determine the function of autophagy and ferroptosis in response to arginine deprivation in SCLC. 2) Determine mechanisms of resistance to ADI-PEG20 and test new combination strategies to increase the efficacy of ADI-PEG20 treatment. This approach is innovative because we will employ our immune-competent GEMM of MYC-driven SCLC and new human PDX that recapitulate key features of the human disease. We will integrate state-of-the-art technologies in metabolite profiling and single cell RNA-seq to understand the mechanisms of resistance to arginine deprivation in vivo. This research is significant because arginine deprivation is being tested in numerous clinical trials in various cancer types and we are currently designing new clinical trials for ADI-PEG20 in SCLC. A better understanding of the functions of arginine deprivation may improve treatment of MYC-driven cancers and lead to more effective combination treatment strategies.

项目总结