title: Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302.
abstract: Previous reports have suggested that the hypoxic microenvironment provides a niche that supports tumor stem cells, and that this might explain clinical observations linking hypoxia to metastasis. To test this, we examined the effects of a hypoxia-activated prodrug, TH-302, on the tumor-initiating cell (TIC) frequency of patient-derived pancreatic xenografts (PDX).The frequencies of TIC, measured by limiting dilution assay, varied widely in 11 PDX models, and were correlated with rapid growth but not with the levels of hypoxia. Treatment with either TH-302 or ionizing radiation (IR), to target hypoxic and well-oxygenated regions, respectively, reduced TIC frequency, and the combination of TH-302 and IR was much more effective in all models tested. The combination was also more effective than TH-302 or IR alone controlling tumor growth, particularly treating the more rapidly-growing/hypoxic models. These findings support the clinical utility of hypoxia targeting in combination with radiotherapy to treat pancreatic cancers, but do not provide strong evidence for a hypoxic stem cell niche.
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ines
authors.initials: I
authors.lastname: Lohse
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Rasowski
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Pinjiang
authors.initials: P
authors.lastname: Cao
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Radiation Medicine Program, Toronto, Ontario, Canada.|Department of STTARR Innovation Center, Toronto, Ontario, Canada.
authors.forename: Trevor
authors.initials: T
authors.lastname: Do
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Pathology, University Health Network, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, Toronto, Ontario, Canada.|Department of Radiation Oncology, Toronto, Ontario, Canada.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Hedley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009593:Nitroimidazoles / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010752:Phosphoramide Mustards / Q000494:pharmacology*; D011355:Prodrugs / 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
keywords: TH-302; hypoxia; pancreatic cancer; patient-derived xenograft; tumor-initiating cells