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：
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
项目类别：
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

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.

项目概要小细胞肺癌 (SCLC) 是一种高度侵袭性的神经内分泌肺癌，导致超过 30,000 美国每年都有死亡人数。在没有获批的靶向治疗的情况下，SCLC 的两年生存率约为 6% 超出了最近批准的免疫疗法。 SCLC 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。 SCLC 治疗的一个主要未满足需求是确定新的治疗靶点和治疗策略。 SCLC 历来被视为单一疾病没有患者分层的疾病。 SCLC 由不同的 MYC 家族成员（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 具有不同的分子特征对靶向治疗具有独特脆弱性的表型。我们对以下对象进行了无偏见的代谢物分析： MYC 与 MYCL 驱动的 SCLC 亚型相比，发现它们在代谢上是不同的。使用人体细胞我们发现，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） MYC 驱动的 SCLC 独特地依赖于氨基酸精氨酸。聚乙二醇化精氨酸消耗精氨酸脱亚胺酶 (ADI-PEG20) 是我们在 GEMM 中测试过的超过 25 种药物组合中最有效的药物。一致的是，MYC 驱动的 SCLC 降低了 ASS1 的表达，ASS1 是合成精氨酸所需的酶。在初步数据显示，我们发现用 ADI-PEG20 处理的 MYC 驱动的肿瘤细胞会发生自噬并铁死亡。经过戏剧性的初始反应后，肿瘤最终随着 ASS1 的重新表达和代谢的复发而复发。通过一碳、多胺和铁死亡相关途径的变化进行重编程。我们假设 MYC 驱动的 SCLC 中的精氨酸剥夺会促进自噬和铁死亡，并且抑制铁死亡将提高 ADI-PEG20 的功效。我们还假设在 ADI-PEG20 耐药期间，重新 ASS1 的表达会导致代谢重编程，而这种重编程可以通过针对新的代谢途径来阻断。为了检验这些假设，我们的目标是：1）确定自噬和铁死亡响应的功能 SCLC 中精氨酸剥夺。 2) 确定 ADI-PEG20 的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，因为我们将采用 MYC 驱动的 SCLC 的免疫功能 GEMM 和新的人类 PDX 来概括关键人类疾病的特点。我们将在代谢物分析和单一分析中整合最先进的技术细胞 RNA-seq 了解体内精氨酸剥夺的抵抗机制。这项研究是意义重大，因为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，我们目前正在设计 ADI-PEG20 在 SCLC 中的新临床试验。更好地理解其功能精氨酸剥夺可能改善 MYC 驱动的癌症的治疗并导致更有效的组合治疗策略。