Mechanisms of Arginine Deprivation in Small Cell Lung Cancer

小细胞肺癌中精氨酸剥夺的机制

• 批准号: 10701855
• 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
• 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/10701855
• 关键词: ASCL1 gene; ATAC-seq; Address; Amino Acids; Anabolism; Arginine; Arginine deiminase; Autophagocytosis; BETA2 protein; Biological Markers; Cancer Patient; Carbon; Cell Death; Cell Death Induction; Cell Line; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Chloroquine; Circulation; Clinical Trials; Combined Modality Therapy; Congresses; Data; Disease; Disease model; Drug Combinations; Environment; Enzymes; Extensive Stage; Family; Family member; Ferritin; Genetic; Genetically Engineered Mouse; Human; Human Cell Line; Immune system; Immunocompetent; Immunotherapy; Ireland; Knock-out; 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; 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; Xenograft Model; argininosuccinate synthase; cancer cell; cancer subtypes; cancer therapy; cancer type; chemotherapy; deprivation; design; erastin; human disease; improved; in vivo; innovation; lung cancer cell; mTOR inhibition; molecular phenotype; molecular subtypes; mortality; neoplastic cell; new therapeutic target; novel; patient derived xenograft model; patient stratification; pharmacologic; resistance mechanism; response; single-cell RNA sequencing; small cell lung carcinoma; standard of care; targeted treatment; transcription factor; transcriptome sequencing; treatment strategy; tumor

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.

项目摘要 小细胞肺癌（SCLC）是一种高度侵袭性的神经内分泌肺肿瘤， 每年在美国死亡。SCLC的两年生存率约为6%，没有批准的靶向治疗 除了最近批准的免疫疗法。SCLC最初对化疗高度敏感，但很快就能缓解。 产生耐药性，导致约12个月内死亡。SCLC治疗的一个主要未满足的需求是 确定新的治疗靶点和治疗策略。SCLC在历史上一直被视为单一的 没有患者分层的疾病。SCLC由不同的MYC家族成员（MYCL或MYC）驱动， 是出了名的难下药我们和其他人发现MYC和MYCL驱动的SCLC具有不同的分子生物学特性， 对靶向治疗具有独特脆弱性的表型。我们进行了公正的代谢物分析， MYC与MYCL驱动的SCLC亚型，发现它们在代谢上不同。使用人体细胞 细胞系、基因工程小鼠模型（GEMM）和人类患者来源的异种移植物（PDX），我们发现 MYC驱动的SCLC是唯一依赖于精氨酸的。精氨酸耗竭伴聚乙二醇化 精氨酸脱亚胺酶（ADI-PEG 20）是我们在GEMM中测试的> 25种药物组合中最有效的药物。 一致地，MYC驱动的SCLC具有降低的ASS 1表达，该酶是合成精氨酸所需的。在 初步数据，我们发现用ADI-PEG 20处理的MYC驱动的肿瘤细胞经历自噬， 铁性下垂在戏剧性的初始反应后，肿瘤最终复发，伴有ASS 1和代谢产物的重新表达。 重编程与一碳，多胺，和铁相关途径的变化。我们假设 MYC驱动的SCLC中精氨酸剥夺通过铁凋亡促进自噬和死亡， 铁凋亡将提高ADI-PEG 20的功效。我们还假设，在ADI-PEG 20抵抗期间， ASS1的表达导致代谢重编程，这可以通过靶向新的代谢途径来阻断。 为了验证这些假设，我们的目标是：1）确定自噬和铁凋亡在反应中的作用 精氨酸缺乏的影响。2)确定ADI-PEG 20耐药机制并测试新的 联合策略以提高ADI-PEG20治疗的功效。这种方法是创新的，因为 我们将使用我们的MYC驱动的SCLC的免疫活性GEMM和新的人类PDX， 人类疾病的特征。我们将整合最先进的代谢物分析技术和单一 cell RNA-seq，以了解体内精氨酸剥夺抗性的机制。本研究是 这是因为精氨酸剥夺正在各种癌症类型的许多临床试验中进行测试， 我们目前正在设计ADI-PEG 20在SCLC中的新临床试验。更好地理解 精氨酸剥夺可以改善MYC驱动的癌症的治疗，并导致更有效的组合 治疗策略。