2020 Grantee: Susan Bates, MD
Research Project: Exploiting a Metabolic Vulnerability Created by Epigenetic Therapy
Award: 2020 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2020 – June 30, 2022
Dr. Susan Bates received her MD degree from the University of Arkansas School of Medicine and completed her clinical training in internal medicine at Georgetown University in Washington, D.C., and in medical oncology at the National Cancer Institute (NCI) in Bethesda, MD. Dr. Bates was Head of the Molecular Therapeutics Section in the Developmental Therapeutics Branch of the Center for Cancer Research before moving to Columbia University, where she currently treats patients with pancreatic cancer and cholangiocarcinoma.
During her years at the NCI, Dr. Bates led a highly successful translational research program focused on mechanisms of multidrug resistance and approaches to improve the activity of drugs that modify epigenetics. Epigenetics are changes in gene expression that don’t alter the sequence of the genetic code. Dr. Bates’ laboratory effort focuses on epigenetic agents and translational studies on drug-resistant cancers including T-cell lymphomas, cholangiocarcinoma and neuroendocrine cancer – with a particular focus on developing therapies for pancreatic cancer. Her work is dedicated to finding cancer-fighting agents that, alone or in combination, improve the options available for difficult-to-treat cancers.
Prior to this award, Dr. Bates served as the co-principal investigator for a 2017 PanCAN Translational Research Grant, alongside Dr. Timothy Wang, funded by Tap Cancer Out.
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.