title: Using a novel NQO1 bioactivatable drug, beta-lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer.
abstract: Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor versus associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2O2) levels; normal tissues are spared by low NQO1 and high catalase expression. DNA damage created by ARQ761 in pancreatic cancer cells "hyperactivates" PARP1, causing metabolic catastrophe and NAD ± keresis cell death. NQO1: catalase levels (high in tumor, low in normal tissue) are an attractive therapeutic window to treat pancreatic cancer. Based on a growing body of literature, we are leading a clinical trial to evaluate the combination of ARQ761 and chemotherapy in patients with pancreatic cancer.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.|Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Muhammad Shaalan
authors.identifier: http://orcid.org/0000-0002-3754-6627
authors.initials: MS
authors.lastname: Beg
authors.affiliation: Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.|Departments of Pharmacology and Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Silvers
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.|Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: David E
authors.initials: DE
authors.lastname: Gerber
authors.affiliation: Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Joyce
authors.initials: J
authors.lastname: Bolluyt
authors.affiliation: Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.|Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Venetia
authors.initials: V
authors.lastname: Sarode
authors.affiliation: Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Farjana
authors.initials: F
authors.lastname: Fattah
authors.affiliation: Departments of Pharmacology and Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.|Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Deberardinis
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Merritt
authors.affiliation: Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Clinical Pharmacology & Experimental Therapeutics Center, Texas Tech University Health Sciences Center, School of Pharmacy, Dallas, Texas.
authors.forename: Richard
authors.initials: R
authors.lastname: Leff
authors.affiliation: Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.affiliation: Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.|Departments of Pharmacology and Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
mesh_terms: D000418:Albumins / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017321:Clinical Trials, Phase I as Topic; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D009285:Naphthoquinones; D003841:Deoxycytidine; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D017239:Paclitaxel; D000093542:Gemcitabine
keywords: cancer metabolism; experimental therapeutics; hyperpolarization; pancreatic cancer; β-lapachone