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Stromal metabolism promotes therapeutic resistance in pancreatic cancer

基质代谢促进胰腺癌的治疗抵抗

基本信息

批准号：
10596979
负责人：
Costas Andreas Lyssiotis
金额：
$ 39.21万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596979
关键词：
Alleles Anabolism Biochemical Blood Vessels Cell Proliferation Cells Clinical Trials Coculture Techniques Communication Deposition Desmoplastic Disease Environment Excision Extracellular Matrix Fibroblasts Generations Genetic Genetically Engineered Mouse Goals Growth Homeostasis Human Hypoxia Immunocompetent Immunotherapy Impairment In Vitro Isotopes KRASG12D Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Mitochondrial Aspartate Aminotransferase Modeling Modernization Mutation NADH NADH oxidase Neoplasm Transplantation Non-Malignant Nutrient Oncogenic Organelles Organoids Oxidation-Reduction Oxygen Pancreatic Ductal Adenocarcinoma Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Physiological Proliferating Property Pyruvate Pyruvate Metabolism Pathway Radiation Reaction Reporting Research Proposals Resistance Role Scheme Series Signal Pathway Signal Transduction Stromal Cells Survival Rate System Techniques Testing Therapeutic Translations Transplantation Treatment Efficacy Tumor Promotion Vascularization Work Xenograft procedure cancer cell cancer type cell growth cell type chemotherapy clinical application density effective therapy efficacy evaluation human model improved outcome in vivo inhibitor insight interest metabolomics mitochondrial metabolism mouse model novel oxidation pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm pharmacologic pressure prevent targeted agent targeted treatment therapy resistant treatment strategy tumor tumor growth tumor metabolism tumor microenvironment tumor xenograft wasting

项目摘要

ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is a devastating disease with a five-year survival rate below 10%. Modern advances in chemotherapy and immunotherapy have yet to provide effective treatments. While oncogenic mutations in Kras are nearly universal in PDA, to date Kras remains undruggable. Clearly, new strategies are needed to develop more effective strategies to improve outcomes for patients with PDA. Metabolic pathways utilized by PDA cells present attractive targets to exploit therapeutically. The cells in a pancreatic tumor are nutrient-deprived and persist in a hypoxic environment. High intratumoral pressure caused by excessive extracellular matrix deposition from the cancer-associated fibroblasts (CAFs) prevents proper vascularization, nutrient delivery, and waste removal. Predictably, PDA cells hijack normal metabolic pathways to meet the biosynthetic and energetic demands required to survive and proliferate. According to this framework, several agents that target pancreatic tumor metabolism are being explored in clinical trials. However, PDA cells also support their metabolic demands via interaction with non-malignant cells. Thus, strategies targeting tumor metabolism must also take into consideration the role of the diverse cell types in the tumor microenvironment. Consistent with previous work, we observed that inhibition of mitochondrial metabolism is profoundly growth inhibitory to PDA cells in culture. Yet, we more recently found that PDA tumors are resistant to mitochondrial- targeted therapies in vivo. Through a series of biochemical and metabolomic co-culture studies, we found that pancreatic CAFs promotes resistance to mitochondrial inhibition. We then identified pyruvate as the single factor in CAF media that restored PDA cell proliferation upon mitochondrial inhibition. In this research proposal, we will define how pyruvate is made and released by CAFs and how pyruvate is obtained and utilized by PDA cells to promote resistance to mitochondrial inhibitors. We will also test the hypothesis that pyruvate release is a CAF property engaged by signaling pathways promoted within pancreatic tumors. These studies will be accomplished using metabolomics techniques in combination with inhibitors of metabolism and signal transduction. In parallel, we will disrupt this pyruvate crosstalk pathway in human patient-derived organoid models and in orthotopic transplant mouse models to determine the translation value. The application of insights from these studies could have an immediate impact on patients, as mitochondrially-targeted therapies are being tested in clinical trials for PDA and other cancers. A means to predict activity of mitochondrially- targeted agents based on tumor CAF content or CAF properties would increase the utility of these agents.

摘要