2020 Grant Recipient Susan Bates, MD

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2020 & 2022 Grantee: Susan Bates, MD

Columbia University
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
Amount: $500,000

Award Extension: 2022 Pancreatic Cancer Action Network Translational Research Grant Extension
Award Period: July 1, 2022 – June 30, 2023
Amount: $250,000

Biographical Highlights

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 Irving Medical Center, where she currently treats patients with pancreatic and biliary cancers.

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. Dr. Bates’ laboratory is located at the James J. Peters VA Medical Center in Bronx, NY.

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.

Project Overview

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.

Project Overview: 2022 Extension

Among the functions of mutant KRAS, the most frequently mutated protein in pancreatic tumors, is altering the cancer cells’ ability to undergo metabolism – the breakdown of nutrients for energy – compared to healthy cells. Because pancreatic cancer cells grow so rapidly, they need sustained levels of nutrients and efficient strategies to metabolize those nutrients.

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 to starve the cancer cells of nutrients so that they can’t survive. This strategy is based on the interaction of two drugs that work together to lethally interfere with cellular metabolism. Early experiments have suggested that these two drugs are synergistic, which means their combined effect is stronger than adding each individual drug’s effect together.

The two drugs being utilized are romidepsin (a drug known as a histone deacetylation inhibitor) and MZ735 (a drug known as 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.

At the time of her original grant application, Dr. Bates had data suggesting that combining MZ735 with romidepsin causes marked cell death in pancreatic cancer cells. With funding from PanCAN, the Bates lab has taken a deeper dive into this two-drug approach to better understand the mechanism of synergy and to conduct preclinical experiments that will lead to a clinical trial of this drug combination.

Based on the project’s promising results to date, Dr. Bates’ one-year extension of her Translational Research Grant will support the completion of the animal studies needed to find a safe dose for this treatment and determine the appropriate sequence between the investigational drugs. Whereas the treatment has been administered intraperitoneally (injected into the abdomen) as a lab-based strategy for their mouse studies, Dr. Bates is also evaluating whether this can be a feasible delivery approach in patients with peritoneal metastasis of their pancreatic cancer.

This extension will also allow the team to further explore the mechanisms that make romidepsin-MZ735 a promising drug combination. For example, while the team’s focus has been on how the drugs influence the cells’ metabolism, there is evidence to suggest they may also impact the cells’ ability to repair DNA damage. Understanding the exact way the drugs work in cells and in mice is necessary before embarking on clinical trials in patients. Collectively, this knowledge will not only pave the way for a clinical trial of this drug combination, but it could also help inform the development of future therapies for pancreatic cancer.

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.