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）是一种高度侵略性的神经内分泌肺肿瘤，负责超过30,000 美国每年死亡。 SCLC的两年生存率约为6％，没有批准的靶向疗法 除了最近批准免疫疗法之外。 SCLC最初对化学疗法有很高的反应，但迅速 发展抗性导致约12个月内死亡。 SCLC治疗的主要未满足的需求是 确定新的治疗靶标和治疗策略。 SCLC历史上一直被视为一个 没有患者分层的疾病。 SCLC由不同的MYC家庭成员（MYCL或MYC）驱动， 众所周知，很难吸毒。我们和其他人表明MYC和MYCL驱动的SCLC具有独特的分子 具有独特脆弱性靶向疗法的表型。我们对公正的代谢物分析进行 MYC与SCLC的MYCL驱动的亚型，发现它们在代谢上与众不同。使用人类细胞 线，遗传工程的小鼠模型（GEMM）和人类患者衍生的异种移植物（PDX），我们发现 MYC驱动的SCLC独特地取决于氨基酸精氨酸。精氨酸枯竭 精氨酸脱节酶（ADI-PEG20）是我们在GEMM中> 25种药物组合中测​​试的最有效的药物。 一致地，MYC驱动的SCLC具有降低的ASS1表达，即合成精氨酸所需的酶。在 初步数据，我们发现用ADI-PEG20处理的MYC驱动的肿瘤细胞经历自噬和 铁凋亡。经过戏剧性的初始反应后，肿瘤最终随着ASS1和代谢的重新表达而复发 重编程，随着单碳，多胺和与铁毒相关的途径的变化。我们假设这一点 MYC驱动的SCLC中的精氨酸剥夺可促进自噬和死亡，并抑制 铁凋亡将提高ADI-PEG20的功效。我们还假设，在ADI-PEG20抗性期间， ASS1的表达导致代谢重编程可以通过靶向新的代谢途径来阻止。 为了检验这些假设，我们的目标是：1）确定自噬和铁铁作用的功能 在SCLC中剥夺精氨酸。 2）确定对ADI-PEG20抗性的机制并测试新的 增加ADI-PEG20治疗功效的组合策略。这种方法是创新的，因为 我们将采用MYC驱动的SCLC和新的Human PDX的免疫能力的GEMM，可以概括钥匙 人类疾病的特征。我们将在代谢物分析中整合最先进的技术和单一的技术 细胞RNA-seq了解体内精氨酸剥夺的抗性机制。这项研究是 意义重大，因为在各种癌症类型的许多临床试验中都在测试精氨酸的剥夺 我们目前正在SCLC设计ADI-PEG20的新临床试验。更好地理解 精氨酸剥夺可以改善对MYC驱动的癌症的处理，并导致更有效的组合 治疗策略。