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.

项目摘要 胰腺导管腺癌（PDA）仍然是最棘手的癌症之一， 5年生存率低于9％。令人震惊的是，胰腺癌的发生率是 在过去的20年中，年轻人的发病率急剧增加。 营养不良和肥胖可能是罪魁祸首，肥胖和糖尿病独立授予 PDA的风险增加，但机制仍不清楚。 分支链氨基酸（BCAA）已成为一种潜在的重要联系 饮食，系统性代谢和PDA。我们已经在以前的工作和初步中证明了 BCAA被胰腺大量消耗的数据，在那里他们为 TCA周期和乙酰辅酶A池。我们最近还表明乙酰辅酶A 代谢在促进胰腺肿瘤开始中起关键作用，导致假设 有效的胰腺肿瘤发生需要BCAA代谢。因此，一个主要目标 这笔赠款将是测试BCAA分解代谢在胰腺促进腺泡细胞中的作用 塑性和肿瘤形成。我们将使用最先进的体内同位素示踪剂方法 阐明胰腺中BCAA的命运。我们还将采用营养，遗传（使用 两种新型小鼠模型）以及定义BCAA作用的药理方法 胰腺功能和肿瘤发生中的分解代谢。 与正常的胰腺细胞相反，将BCAA用作燃料来源被认为是 随着胰腺癌的发展而受到抑制。但是，BCAA是重要的生物标志物 PDA的PDA，循环水平在PDA诊断之前数年提高，这表明风险可能 机械上与肿瘤起始不同。 BCAA在肥胖和 糖尿病，它们促进胰岛素分泌和胰岛素抵抗，促进 高胰岛素状态。胰岛素本身是促进合成代谢信号传导和 PDA细胞中的代谢。因此，我们的第二个主要目标是评估系统性的贡献 BCAA水平和PDA肿瘤生长的高胰岛素血症。我们将操纵系统性BCAA 通过营养，遗传和药理方法测试对肿瘤影响的水平 生长。然后，我们将直接查询胰岛素对PDA细胞和癌症相关的影响 成纤维细胞（CAF），以及减少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测试靶向BCAA代谢的潜力。 这些研究将深入了解BCAA在多步PDA肿瘤发生中的作用 并可能导致这种致命疾病的新型治疗策略。