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: 10295695
• 负责人: Trudy Gale Oliver
• 金额: $ 36.91万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295695
• 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

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癌，其发病率超过30,000。 美国每年的死亡人数。在没有批准靶向治疗的情况下，小细胞肺癌的两年存活率为~6% 除了最近批准的免疫疗法之外。小细胞肺癌最初对化疗高度敏感，但很快 产生耐药性，导致约12个月内死亡。小细胞肺癌治疗的一个主要未得到满足的需求是 确定新的治疗靶点和治疗策略。SCLC历来被视为单一的 疾病无患者分层。SCLC由不同的MYC家族成员(MYCL或MYC)推动， 是出了名的难以下药。我们和其他人发现MYC和MYCL驱动的小细胞肺癌具有不同的分子 对靶向治疗具有独特易感性的表型。我们进行了无偏见的代谢物分析 MYC和MYCL驱动的小细胞肺癌亚型，发现它们在代谢上是不同的。使用人类细胞 基因工程小鼠模型(GEMM)和人类患者来源的异种移植(PDX)，我们发现 这种由MYC驱动的SCLC是唯一依赖于氨基酸精氨酸的。聚乙二醇化精氨酸耗竭 精氨酸脱亚胺酶(ADI-PEG20)是我们在GEMM中测试的25种药物组合中最有效的药物。 一直以来，MYC驱动的SCLC降低了ASS1的表达，ASS1是合成精氨酸所需的酶。在……里面 初步数据，我们发现经ADI-PEG20处理的MYC驱动的肿瘤细胞经历了自噬和 铁性下垂。在最初戏剧性的反应后，肿瘤最终复发，ASS1和新陈代谢重新表达 通过一碳、多胺和铁下垂相关通路的改变进行重新编程。我们假设 在MYC驱动的小细胞肺癌中，精氨酸剥夺促进了自噬和铁性下垂导致的死亡，并且抑制 铁性下垂将提高ADI-PEG20的疗效。我们还假设，在ADI-PEG20抵抗期间，Re- ASS1的表达导致代谢重新编程，这种重新编程可以通过靶向新的代谢途径来阻止。 为了验证这些假说，我们的目标是：1)确定自噬和铁性下垂的反应功能 与小细胞肺癌患者精氨酸缺乏有关。2)确定对ADI-PEG20的抗性机制，并检测新的 提高ADI-PEG20治疗疗效的联合策略。这种方法是创新的，因为 我们将使用我们的免疫活性GEMM-MYC驱动的SCLC和概括关键的新的人类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 细胞RNA-seq以了解体内对精氨酸剥夺的抵抗机制。这项研究是 重要的是，精氨酸剥夺正在各种癌症类型的大量临床试验中进行测试 我们目前正在为小细胞肺癌的ADI-PEG20设计新的临床试验。更好地理解网络的功能 精氨酸剥夺可能会改善MYC驱动的癌症的治疗，并导致更有效的联合 治疗策略。