Branched chain amino acids in pancreatic carcinogenesis

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY The incidence of pancreatic ductal adenocarcinoma (PDA) has been rising in recent decades, likely attributable in part to increased rates of obesity, which is a known risk factor. Branched chain amino acids (BCAAs) are consumed avidly by the healthy exocrine pancreas, where they are used for both protein synthesis and oxidized in mitochondria. In the catabolic pathway, BCAAs first undergo transamination mediated by branched chain amino acid transaminase (BCAT) enzymes, generating branched chain á-ketoacids (BCKAs). BCKAs are committed to oxidation in mitochondria by the branched chain ketoacid dehydrogenase (BCKDH) complex. The kinase BCKDK phosphorylates BCKDHA to suppress BCAA breakdown, and accordingly inhibition of BCKDK promotes BCAA catabolism. BCKDK is a promising therapeutic target for treating metabolic diseases and a BCKDK inhibitor is in clinical trials for treating adults with heart failure. In the first phase of this grant, we have investigated the role of BCAA catabolism in pancreatic neoplasia, finding that BCKDK inhibition reduces formation of pancreatic intraepithelial neoplasia (PanIN). Unexpectedly, this appears to occur independently of promoting BCAA catabolism within pancreatic epithelial cells themselves. In this grant application, we propose to define the mechanisms through which promotion of BCAA catabolism impedes pancreatic neoplasia, examining both cell intrinsic mechanisms and effects on the local microenvironment. A key goal of this research program is to test the potential to target this pathway therapeutically to reduce incidence in contexts of elevated PDA risk such as in diet induced obesity. Because this project centers on early-stage neoplasia—where well-validated genetic mouse models exist—and on whole-body metabolic regulation and intercellular metabolic interactions, which can only be studied in intact organisms, mouse models are the most appropriate system for much of the proposed work. This work will also be complemented with the use of human cell and organoid models to ensure human relevance

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Although obesity has been established as a major risk factor for pancreatic ductal adenocarcinoma, the mechanisms through which metabolic factors contribute to carcinogenesis remain poorly understood. We have observed that promoting catabolism of branched chain amino acids (BCAAs: leucine, valine, isoleucine) through inhibition of the kinase BCKDK reduces the formation of oncogene-induced premalignant lesions. We propose to define the cell intrinsic and microenvironmental roles of BCKDK in pancreatic neoplasia, and to test the potential to target this pathway therapeutically to reduce tumor development.