Exploiting a Metabolic Vulnerability Created by Epigenetic Therapy

Pancreatic cancer (ductal adenocarcinoma) is characterized by cancer-inducing, activating KRAS mutations that support the growth and survival of a tumor with one of the fastest growth rates among human solid tumors. Among the functions of mutant KRAS is inducing reprogrammed metabolism, the breakdown of nutrients for energy, via several downstream pathways. Dr. Bates and her team have identified a strategy that interferes with the high metabolic need of pancreatic cancer cells by systematically depleting essential nutrients from the cancer cells. The goal is starvation of nutrients that will lead to cancer cell death. This strategy is based on the interaction of two drugs that work together to lethally interfere with cellular metabolism. Early experiments have suggested that the drugs are synergistic, which means their combined effect is stronger than adding each individual drug’s effect together. The two drugs being utilized are a histone deacetylation inhibitor and a protein translation inhibitor. Blocking histone deacetylation results in global hyperacetylation that is thought to limit cell growth or induce cell death. The protein translation inhibitor will reduce levels of a protein called MYC with cancer-causing activities. Dr. Bates and colleagues discovered that combining a protein translation inhibitor able to reduce MYC levels with the histone deacetylase inhibitor romidepsin causes marked cell death in pancreatic cancer cells. Through this project, the investigators propose to validate and extend these results, understand the mechanism of synergy and carry out preclinical experiments that will lead to a clinical trial of this drug combination.