Project 3: The AMPK Autophagy Pathway as a Metabolic Liability in Pancratic Ductal Adenocarcinoma

项目 3：AMPK 自噬途径作为胰腺导管腺癌的代谢负担

基本信息

批准号：
10629065
负责人：
Reuben Shaw
金额：
$ 46.68万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-06 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629065
关键词：
Address Adenocarcinoma Affect Alanine Attenuated Automobile Driving Autophagocytosis Autophagosome Biochemical Biological Availability Cell Compartmentation Cell Nucleus Cell Survival Cell physiology Cells Characteristics Chemoresistance Chloroquine Clinic Clinical Collaborations DNA Damage Desmoplastic Development Disease Disease Progression Duct (organ) structure Enzymes Epigenetic Process Epithelial Cells Epithelium FRAP1 gene Fibroblasts Gene Expression Genetic Genetic Transcription Genetically Engineered Mouse Growth HDAC3 gene Histone Deacetylase Human KPC model Knowledge Lesion MEK inhibition MEKs Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Mediator Metabolic Metabolic stress Metabolism Modality Mus Mutation Myelogenous Normal Cell Nutrient Nutrient availability Organelles Organoids Pancreas Transplantation Pancreatic Ductal Adenocarcinoma Paracrine Communication Pathway interactions Performance Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Population Proteins Recycling Regulation Reporter Reporting Research Resistance Role Signal Transduction Source Stress Stromal Cells Therapeutic Toxic effect Translating Up-Regulation Vascularization Work Xenograft procedure antagonist checkpoint inhibition chemotherapy defined contribution effective therapy efficacy evaluation epigenetic regulation experimental study in vivo inhibition of autophagy inhibitor kinase inhibitor mTOR inhibition mouse model neoplastic cell novel novel strategies pancreatic ductal adenocarcinoma model pancreatic neoplasm pharmacologic programs response synergism targeted treatment therapeutic target therapy resistant tool transcriptional reprogramming treatment response treatment strategy tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY – Project 3: Autophagy Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest forms of cancer with few effective therapies. The poor performance of current treatments is partly due to metabolic adaptations in both the tumor and stromal compartments, such as the recycling of proteins and organelles through increased autophagy. As a hallmark of PDA, autophagy provides a key source of nutrients in the restrictive tumor microenvironment (TME). Accumulating evidence also implicates the autophagy program as a critical mediator of resistance to numerous therapeutics, including chemotherapy, MEK inhibitors, and immune checkpoint inhibition. Foundational research from the Shaw group decoded key biochemical steps involved in the initiation of autophagy, including upstream regulation of AMPK and its downstream activation of ULK1 and ULK2, the kinases that drive autophagosome formation. More recent work from the Shaw group has also revealed that AMPK can block the translocation of Class II HDACs to the nucleus. Despites these advances, the specific roles of AMPK in autophagy control and epigenetic regulation have never been investigated in pancreatic cancer. Moreover, while autophagy has emerged as an attractive therapeutic target in pancreatic cancer, efforts to translate this to the clinic have been hindered by a lack of autophagy-specific inhibitors, with only broad lysosomotropic agents like chloroquine available for study. To address this gap, the lab has developed novel, bioavailable inhibitors of ULK1 and ULK2, two of only three druggable enzymes specific to the autophagy pathway. These inhibitors provide critical tools with which to dissect the contributions of autophagy to PDA growth and form the basis for a new approach for overcoming therapeutic resistance in this deadly disease. Here, experiments proposed in Aim 1 will define when and where different facets of AMPK signaling and autophagy are activated during disease progression in the autochthonous mouse KPC model of PDA. In collaboration with Project 1, conditional deletions of AMPK or its downstream targets ULK1/2 and HDAC3 will be used to evaluate their contribution to metabolic adaptations driving tumor growth and epigenetic changes mediating tumor cellular functions. In addition, the contribution of AMPK pathway components in supporting PDA resistance to chemotherapeutics and targeted therapies will be dissected. In Aim 2, the roles of canonical and noncanonical autophagy in non-cell autonomous support of pancreatic tumor growth will be delineated by comparing stromal deletion of ULK1/2 and ATG7. In addition, experiments will dissect cell-specific requirements for autophagy within the fibroblast and myeloid compartments in supporting PDA therapeutic resistance. In Aim 3, the Shaw lab’s novel, bioavailable ULK inhibitor will be used to determine how selective inhibition of autophagy impacts PDA growth through reprogrammed tumor and stromal cell function. The potential of ULK inhibitors in rescuing autophagy-dependent therapeutic resistance to chemotherapies, MEK inhibitors, and immune checkpoint inhibition will be explored.

项目摘要 - 项目3：自噬胰腺导管腺癌（PDA）是最致命的癌症之一，几乎没有有效的疗法。当前治疗的表现不佳部分是由于肿瘤和基质中的代谢适应隔室，例如通过增加的自噬来回收蛋白质和细胞器。作为一个标志 PDA自噬为限制性肿瘤微环境（TME）提供了关键的营养来源。累积证据还将自噬程序作为对众多抵抗的关键调解人的实现剧院，包括化学疗法，MEK抑制剂和免疫检查点抑制作用。基础研究从邵氏组解码自噬倡议中涉及的钥匙生化步骤，包括上游 AMPK的调节及其下游激活ULK1和ULK2（驱动自噬体的激酶）形成。 Shaw Group的最新工作还表明，AMPK可以阻止易位 II类HDACS到核。在这些进步中，AMPK在自噬控制中的具体角色和胰腺癌从未研究过表观遗传调节。而且，自噬具有成为胰腺癌中有吸引力的治疗靶标，将其转化为诊所的努力已经是由于缺乏自噬特异性抑制剂而受到阻碍，只有宽阔的溶酶体像氯喹可用于学习。为了解决这一差距，该实验室已经开发了新颖的，ULK1和ULK2的可生物利用抑制剂，自噬途径特有的只有三种可吸毒的酶中的两种。这些抑制剂提供关键的工具剖析自噬对PDA增长的贡献，并为一种新方法构成基础克服这种致命疾病的治疗性抗性。在这里，AIM 1中提出的实验将定义以及在疾病进展过程中激活AMPK信号传导和自噬的不同方面 PDA的自围小鼠KPC模型。与项目1合作，有条件地删除了AMPK或ITS 下游目标ULK1/2和HDAC3将用于评估其对代谢适应的贡献驱动肿瘤生长和表观遗传变化介导肿瘤细胞功能。另外， AMPK途径成分在支持PDA对化学治疗剂和靶向疗法的耐药性方面将是解剖。在AIM 2中，规范和非规范自噬在非电池自动支持中的作用通过比较ULK1/2和ATG7的基质缺失，将描绘胰腺肿瘤生长。此外，实验将在成纤维细胞和髓样室内剖析自噬的细胞特异性需求支持PDA治疗性抗性。在AIM 3中，将使用Shaw Lab的小说生物可用ULK抑制剂确定选择性抑制自噬如何通过重编程的肿瘤和基质细胞功能。 ULK抑制剂在挽救自噬依赖性治疗性的潜力将探索化学疗法，MEK抑制剂和免疫抑制作用。