title: Evaluation of the "steal" phenomenon on the efficacy of hypoxia activated prodrug TH-302 in pancreatic cancer.
abstract: Pancreatic ductal adenocarcinomas are desmoplastic and hypoxic, both of which are associated with poor prognosis. Hypoxia-activated prodrugs (HAPs) are specifically activated in hypoxic environments to release cytotoxic or cytostatic effectors. TH-302 is a HAP that is currently being evaluated in a Phase III clinical trial in pancreatic cancer. Using animal models, we show that tumor hypoxia can be exacerbated using a vasodilator, hydralazine, improving TH-302 efficacy. Hydralazine reduces tumor blood flow through the "steal" phenomenon, in which atonal immature tumor vasculature fails to dilate in coordination with normal vasculature. We show that MIA PaCa-2 tumors exhibit a "steal" effect in response to hydralazine, resulting in decreased tumor blood flow and subsequent tumor pH reduction. The effect is not observed in SU.86.86 tumors with mature tumor vasculature, as measured by CD31 and smooth muscle actin (SMA) immunohistochemistry staining. Combination therapy of hydralazine and TH-302 resulted in a reduction in MIA PaCa-2 tumor volume growth after 18 days of treatment. These studies support a combination mechanism of action for TH-302 with a vasodilator that transiently increases tumor hypoxia.
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States of America; Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida 33612, United States of America.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Bailey
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Cornnell
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Arig
authors.initials: A
authors.lastname: Ibrahim-Hashim
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Wojtkowiak
authors.affiliation: Threshold Pharmaceuticals, South San Francisco, California 94080, United States of America.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Hart
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Arizona Cancer Center, Hematology/Oncology Section, College of Medicine, University of Arizona, Tucson, Arizona 85724, United States of America.
authors.forename: Rafael
authors.initials: R
authors.lastname: Leos
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Gary V
authors.initials: GV
authors.lastname: Martinez
authors.affiliation: Arizona Cancer Center, Hematology/Oncology Section, College of Medicine, University of Arizona, Tucson, Arizona 85724, United States of America.
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Baker
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States of America; Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply* / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001775:Blood Circulation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D051379:Mice; D009593:Nitroimidazoles / Q000378:metabolism / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000473:pathology*; D010752:Phosphoramide Mustards / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302; D006830:Hydralazine