Branched chain amino acids and pancreatic cancer

支链氨基酸与胰腺癌

• 批准号: 10436144
• 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
• 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/10436144
• 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; Lead; Link; Location; Malignant Neoplasms; Malignant neoplasm of pancreas; Meat Products; Mediating; Metabolic; Metabolism; Metaplasia; Mitochondria; Mus; Nuclear; Obesity; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Patients; Pharmacology; Plasma; Play; Prognosis; Risk; Risk Factors; Role; Signal Transduction; Source; Survival Rate; Testing; Tracer; Unresectable; Work; amino acid metabolism; cancer type; chemotherapy; curative treatments; dietary; improved; in vivo; inhibitor; insight; insulin secretion; insulin signaling; loss of function; mouse model; mutant; novel; novel strategies; novel therapeutic intervention; nutrition; nutrition related genetics; obese person; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pancreatic tumorigenesis; response; standard of care; treatment response; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis; wound healing; young adult

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 胰腺导管腺癌(PDA)仍然是最难治疗的癌症类型之一， 5年存活率低于9%。令人担忧的是，胰腺癌的发病率正在上升 在过去20年中，发病率上升，尤其是在年轻人中的发病率急剧上升。 营养不良和肥胖可能是罪魁祸首，肥胖和糖尿病是独立的诱因。 增加了PDA的风险，但其机制仍不清楚。 支链氨基酸(BCAA)已成为潜在的重要联系 饮食、系统新陈代谢和掌上电脑。我们在以前的工作和初步的工作中已经演示了 支链氨基酸被胰腺贪婪地消耗的数据，在那里它们做出了显著贡献 三氯乙烷循环和乙酰辅酶A池。我们最近还证明了乙酰辅酶A 代谢在促进胰腺肿瘤的发生中起着关键作用，从而导致了这一假说。 支链氨基酸代谢是有效的胰腺肿瘤发生所必需的。因此，一个主要目标是 这笔赠款将用于测试支链氨基酸在胰腺分解代谢促进腺泡细胞生长中的作用。 可塑性和肿瘤形成。我们将使用最先进的活体同位素示踪方法 阐明支链氨基酸在胰腺中的命运。我们还将采用营养、遗传(使用 两种新的小鼠模型)，以及确定支链氨基酸作用的药理学方法 胰腺功能的分解代谢与肿瘤发生。 与正常的胰腺细胞相比，使用支链氨基酸作为燃料来源被认为是 随着胰腺癌的发展而抑制。然而，支链氨基酸是一种重要的生物标志物。 在PDA诊断前几年循环水平升高，表明有可能存在 在机制上不同于肿瘤的启动。支链氨基酸在肥胖和 糖尿病，促进胰岛素分泌和胰岛素抵抗，促进 高胰岛素状态。胰岛素本身作为一种生长因子促进合成代谢信号和 PDA细胞的新陈代谢。因此，我们的第二个主要目标是评估系统 支链氨基酸水平和高胰岛素血症对PDA肿瘤生长的影响。我们将操纵系统性支行氨基酸 通过营养、遗传和药理学方法测试对肿瘤的影响 成长。然后我们将直接询问胰岛素对PDA细胞和与癌症相关的影响 成纤维细胞(CAF)，以及降低高胰岛素血症对肿瘤生长的影响。最后， 我们将通过小鼠临床试验来测试针对支链氨基酸代谢的潜力。 这些研究将为支链氨基酸在多步骤PDA肿瘤发生中的作用提供深入的见解 并可能导致这种致命疾病的新治疗策略。