2014 Grant Recipient David Boothman, PhD

Home Research Research Grants Program Grants Awarded Grants Awarded by Year 2014 Pancreatic Cancer Action Network Research Grants 2014 Grant Recipient David Boothman, PhD

GRANTEE: David Boothman, PhD
Institution: University of Texas Southwestern Medical Center
Research Project: Exploiting an NQO1 ‘kiss of death’ for pancreatic cancer therapy

Award: 2014 Pancreatic Cancer Action Network – Rising Tide Foundation – Gateway Clinical Continuation Research Grant
Award Period: July 1, 2014 – June 30, 2017
Amount: $1,000,000

Click here to download Dr. Boothman’s 2014 Grant Snapshot (pdf)

Institution: University of Texas, Southwestern Medical Center
Research Project: NQO1-mediated ‘Kiss of death’ Targeted Therapy for Pancreatic Cancer
Award: George & June Block Family Foundation – Pancreatic Cancer Action Network – AACR Innovative Grant
Award Period: July 1, 2012 – June 30, 2014
Amount: $200,000

Click here to download Dr. Boothman’s 2012 Grant Snapshot (pdf)

Biographical Highlights
Dr. Boothman received his PhD from the Department of Microbiology at the University of Miami. After a post-doctoral fellowship at the Dana-Farber Cancer Institute, Harvard, in the lab of Dr. Arthur B. Pardee, he joined the Department of Radiation Oncology, University of Michigan, as an Assistant Professor. In 1993, he moved to the Department of Human Oncology at the University of Wisconsin, Madison, and was promoted from Assistant to Associate Professor, with tenure. In 1998, he became Professor of Pharmacology and Radiation Oncology, Case Western Reserve University, where he served as Associate Director for Basic Science. Currently, 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.” His laboratory focuses on understanding cellular stress responses that promote cancer and resist treatment. His lab explores the roles of DNA damage and repair that alter metabolism and the tumor microenvironment. Dr. Boothman’s project builds upon studies supported by his 2012 Pancreatic Cancer Action Network Innovative Grant, generously funded by the George & June Block Family Foundation. The new grant will be funded with the Rising Tide Foundation and Gateway for Cancer Research.

2014 Project Overview
Previously, Dr. Boothman and his colleagues identified a protein, NAD(P)H:quinone oxidoreductase1 (NQO1), that is highly expressed in pancreatic cancer cells compared to normal tissue, including the pancreas. Dr. Boothman’s novel treatment strategy involves exploiting NQO1 expression to metabolize the drug, β-Lapachone (β-Lap, clinical form ARQ761), that then leads to accumulation of hydrogen peroxide specifically in cancer cells. Excess hydrogen peroxide hyper-activates the DNA repair enzyme, PARP1, causing cell death.

Pre-clinical studies at UT Southwestern indicated that b-Lap was efficacious against pancreatic cancers in mice. Dr. Boothman and colleagues will investigate and develop noninvasive technology to examine the effects of β-Lap on glucose metabolism in various mouse models of pancreatic cancer alone and in combination with the chemotherapy drugs, gemcitabine and nab-paclitaxel. Importantly, this grant will support a clinical trial in collaboration with Dr. Shaalan Beg (UT Southwestern) and Dr. Daniel Laheru at Johns Hopkins to test β-Lap and gemcitabine/nab-paclitaxel in 20 patients to determine the safety and feasibility of this novel combination therapy.

2012 Project Overview
In his project generously funded by the George & June Block Family Foundation, Dr. Boothman is searching for ways to exploit characteristics unique to pancreatic cancer cells, to formulate a treatment strategy that selectively targets cancer cells without harming healthy cells. Pancreatic cancer cells express high levels of a protein called NAD(P)H:quinone oxidoreductase 1 (NQO1); in fact, NQO1 levels in pancreatic cancer cells can be 100-times higher than in normal pancreas. Thus, NQO1 is an attractive therapeutic target. Dr. Boothman has already tested a novel drug, called beta-lapachone (ß-lap), that is ‘metabolically activated’ into toxic reactive oxygen species by NQO1. Then, the drug induces cell death only in cancer cells expressing NQO1.

However, preliminary studies have indicated that some of the damage caused by ß-lap can be reversed or repaired in cancer cells. To circumvent this, Dr. Boothman proposes to study the combination of ß-lap with drugs that block DNA repair pathways, and determine if this increases effectiveness in pancreatic cancer cells and mouse models of the disease. Excitingly, ß-lap is currently in early Phase I clinical trials to test for side effects in humans, paving the way for future treatment regimens that include ß-lap alone or in combination.