Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer with a dismal 5-year survival rate of ~10%. The majority of PDAC patients do not present with tumors amenable for surgical resection, and standard-of-care chemotherapy offers only modest improvements in survival. Thus, more effective therapies will be critical to improve patient outcomes, and new targets in the pipeline are needed. Alec Kimmelman and colleagues recently identified that pancreatic cancer cells specifically express and are reliant on the amino acid transporter SLC38A2 for tumor initiation and growth. Altered metabolism is a hallmark of cancer cells, and tumor cells redirect key nutrients to support proliferation. By highly expressing and relying on SLC38A2 to take up alanine from the microenvironment, PDAC cells fuel key metabolic pathways important for proliferation
The goal of this drug discovery award is to identify first-in-class small molecule inhibitors that target SLC38A2. To accomplish this, they will develop a cell-based SLC38A2 uptake assay and screen a large chemical library. Confirmed hits will be subjected to a medicinal chemistry review, further validation, and extensive profiling for in vitro and in vivo activity, specificity, and selectivity in PDAC cells and tumors. Identified leads will serve as chemical scaffolds for future medicinal chemistry-led optimization with the goal of entering clinical development for the treatment of pancreatic cancer.