title: MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts.
abstract: TH-302 is a hypoxia-activated prodrug known to activate selectively under the hypoxic conditions commonly found in solid tumors. It is currently being evaluated in clinical trials, including two trials in Pancreatic Ductal Adenocarcinomas (PDAC). The current study was undertaken to evaluate imaging biomarkers for prediction and response monitoring of TH-302 efficacy in xenograft models of PDAC. Dynamic contrast-enhanced (DCE) and diffusion weighted (DW) magnetic resonance imaging (MRI) were used to monitor acute effects on tumor vasculature and cellularity, respectively. Three human PDAC xenografts with known differential responses to TH-302 were imaged prior to, and at 24 h and 48 hours following a single dose of TH-302 or vehicle to determine if imaging changes presaged changes in tumor volumes. DW-MRI was performed at five b-values to generate apparent diffusion coefficient of water (ADC) maps. For DCE-MRI, a standard clinically available contrast reagent, Gd-DTPA, was used to determine blood flow into the tumor region of interest. TH-302 induced a dramatic decrease in the DCE transfer constant (Ktrans) within 48 hours after treatment in the sensitive tumors, Hs766t and Mia PaCa-2, whereas TH-302 had no effect on the perfusion behavior of resistant SU.86.86 tumors. Tumor cellularity, estimated from ADC, was significantly increased 24 and 48 hours after treatment in Hs766t, but was not observed in the Mia PaCa-2 and SU.86.86 groups. Notably, growth inhibition of Hs766t was observed immediately (day 3) following initiation of treatment, but was not observed in MiaPaCa-2 tumors until 8 days after initiation of treatment. Based on these preclinical findings, DCE-MRI measures of vascular perfusion dynamics and ADC measures of cell density are suggested as potential TH-302 response biomarkers in clinical trials.
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Wojtkowiak
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Gary V
authors.initials: GV
authors.lastname: Martinez
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Cornnell
authors.affiliation: Threshold Pharmaceuticals, South San Francisco, CA, United States of America.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Hart
authors.affiliation: Arizona Cancer Center, Tucson, AZ, United States of America.
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Baker
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Gillies
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D000860:Hypoxia; D008279:Magnetic Resonance Imaging; D051379:Mice; D016513:Mice, SCID; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D010752:Phosphoramide Mustards / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302