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Branched chain amino acids and pancreatic cancer

支链氨基酸与胰腺癌

基本信息

批准号：
10688001
负责人：
Zoltan P Arany
金额：
$ 45.59万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688001
关键词：
ATP Citrate (pro-S)-Lyase Acetyl Coenzyme A Acetylation Acinar Cell Allografting Biological Markers Branched-Chain Amino Acids Catabolism Cell Proliferation Cell Survival Cells Cholesterol Citrates Citric Acid Cycle Clinical Clinical Trials Consumption Cytoplasm Dairy Products Data Development Diabetes Mellitus Diagnosis Diet Disease Duct (organ) structure Environment Epigenetic Process Evaluation Fatty Acids Fatty acid glycerol esters Feedback Fibroblasts Genetic Genetic Models Goals Grant Growth Growth Factor Histones Human Hyperinsulinism In Vitro Incidence Insulin Insulin Resistance Islets of Langerhans Isotopes KRAS2 gene KRASG12D Link Location Malignant Neoplasms Malignant neoplasm of pancreas Meat Products Mediating Metabolic Metabolism Metaplasia Mitochondria Mus Nuclear Nutritional Obesity Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatic duct Patients Plasma Play Prognosis Risk Risk Factors Role Signal Transduction Source Survival Rate Testing Tracer Tumor Promotion Unresectable Work amino acid metabolism cancer type chemotherapy curative treatments dietary gain of function improved in vivo inhibitor insight insulin secretion insulin signaling loss of function mouse model mutant novel novel strategies novel therapeutic intervention nutrition obese person pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm pancreatic tumorigenesis pharmacologic response standard of care treatment response tumor tumor growth tumor initiation tumor progression tumorigenesis wound healing young adult

项目摘要

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) remains one of the most intractable types of cancer, with a 5-year survival rate below 9%. Alarmingly, the incidence of pancreatic cancer is on the rise over the past 20 years, with particularly sharp increases in incidence among young adults. Poor nutrition and obesity are likely culprits, with obesity and diabetes independently conferring increased risk of PDA, but the mechanisms remain unclear. Branched chain amino acids (BCAAs) have emerged as one potentially important link between diet, systemic metabolism, and PDA. We have demonstrated in previous work and preliminary data that BCAAs are avidly consumed by the pancreas, where they contribute prominently to the TCA cycle and to acetyl-CoA pools. We have also recently shown that acetyl-CoA metabolism plays a key role in facilitating pancreatic tumor initiation, leading to the hypothesis that BCAA metabolism is required for efficient pancreatic tumorigenesis. Thus, one major goal of this grant will be to test the role of BCAA catabolism in the pancreas in facilitating acinar cell plasticity and tumor formation. We will use state-of-the-art in vivo isotope tracer approaches to elucidate the fates of BCAAs in the pancreas. We will also employ nutritional, genetic (using two novel mouse models), and pharmacological approaches to define the roles of BCAA catabolism in pancreatic function and tumorigenesis. In contrast to normal pancreatic cells, use of BCAAs as a fuel source is thought to be suppressed as pancreatic cancer develops. Nevertheless, BCAAs are an important biomarker of PDA, with circulating levels elevated years prior to PDA diagnosis, indicating a risk that likely mechanistically differs from that of tumor initiation. BCAAs are also elevated in obesity and diabetes, where they promote insulin secretion and insulin resistance, promoting a hyperinsulinemic state. Insulin itself acts as a growth factor to promote anabolic signaling and metabolism in PDA cells. Our second major goal is thus to evaluate the contribution of systemic BCAA levels and hyperinsulinemia to PDA tumor growth. We will manipulate systemic BCAA levels through nutritional, genetic, and pharmacological approaches to test the impact on tumor growth. We will then query the impact of insulin directly on PDA cells and on cancer-associated fibroblasts (CAFs), along with the impact of reducing hyperinsulinemia on tumor growth. Finally, we will test the potential to target BCAA metabolism through mouse clinical trials. These studies will provide deep insight into the roles of BCAAs in multi-step PDA tumorigenesis and could lead to novel therapeutic strategies for this deadly disease.

项目总结