GRANTEE: David Boothman, PhD
UT Southwestern Medical Center
Co-Principal Investigator: Muhammad Beg, MD
Research Project: Use of PARP1 inhibitors to leverage a tumor-selective ‘kiss of death’
Award: 2015 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2015 – June 30, 2017
Dr. Boothman is the Robert B. and Virginia Payne Professor of Oncology and Pharmacology, and associate director for translational research, Simmons Cancer Center, UT Southwestern at Dallas. He also co-directs the Program in Cell Stress and Cancer Nanomedicine. Dr. Boothman was previously awarded the 2012 Pancreatic Cancer Action Network Innovative Grant, funded by the George & June Block Family Foundation, and the 2015 Clinical Continuation Research Grant, funded with the Rising Tide Foundation and Gateway for Cancer Research.
Dr. Beg is the co-leader of the gastrointestinal (GI) cancers multidisciplinary team at the Simmons Comprehensive Cancer Center. He is principal investigator (PI) on investigator-initiated studies, and serves as the institutional PI for multiple studies in GI cancers, including first-in-class/first-in-man phase I and National Cancer Institute cooperative group studies. Dr. Beg has been attending Dr. Boothman’s lab meeting for the last two years and aiding his lab to translate their findings in the fastest pathway to the clinic.
Nearly all (more than 90 percent) of pancreatic tumors dramatically overexpress levels of a protein called NAD(P)H:quinone oxidoreductase 1 (NQO1). Another protein, catalase, functions to detoxify the byproducts of NQO1-driven reactions. Catalase levels are low in pancreatic cancer cells but high in normal cells, including normal pancreas. Drs. Boothman, Beg, and their research teams seek to exploit the high NQO1:catalase ratio present in pancreatic cancer cells by utilizing a drug called ARQ761 (b-lapachone) that gets broken down by NQO1. One of the by-products of ARQ761 breakdown is hydrogen peroxide, which is toxic to cells. In the absence of catalase to neutralize the hydrogen peroxide, massive DNA damage and cell death occur. By contrast, normal cells have very low levels of NQO1 so they barely break down any ARQ761. And catalase is present to eliminate any hydrogen peroxide that may get produced.
Preliminary evidence has shown that ARQ761 is particularly effective if administered in combination with an inhibitor of a protein called poly (ADP-ribose) polymerase 1 (PARP1). PARP1 facilitates repair of some of the DNA damage caused by the hydrogen peroxide. Inhibiting PARP1 therefore allows DNA damage to accumulate and leads to increased cancer cell death. The purpose of this translational research proposal is to determine the ideal timing and dosing of combining ARQ761 with a PARP1 inhibitor. The second aim of this project seeks to identify biomarkers, or clues found in a tumor sample, that may predict which patients would respond best to this treatment regimen, as well as determine whether a patient currently under treatment is responding well.