MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts

• Published in: PloS one Vol. 11; no. 5; p. e0155289
• Main Authors: Zhang, Xiaomeng, Wojtkowiak, Jonathan W, Martinez, Gary V, Cornnell, Heather H, Hart, Charles P, Baker, Amanda F, Gillies, Robert
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.05.2016; Public Library of Science (PLoS)
• Subjects: Acute effects; Animals; Biological markers; Biology and Life Sciences; Biomarkers; Biomarkers, Tumor - metabolism; Blood flow; Cancer therapies; Cell density; Cell division; Cell Line, Tumor; Chemotherapy; Clinical trials; Diagnosis; Diffusion; Diffusion coefficient; Drug therapy; Female; Gadolinium; Helper cells; Humans; Hypoxia; Image processing; Lymphocytes T; Magnetic resonance; Magnetic Resonance Imaging; Medical research; Medicine and Health Sciences; Metastasis; Mice; Mice, SCID; Nitroimidazoles - pharmacokinetics; Nitroimidazoles - pharmacology; NMR; Nuclear magnetic resonance; Pancreatic cancer; Pancreatic Neoplasms - diagnostic imaging; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Perfusion; Permeability; Phosphoramide Mustards - pharmacokinetics; Phosphoramide Mustards - pharmacology; Physical Sciences; Physiological aspects; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Reagents; Research and Analysis Methods; Solid tumors; Time Factors; Tumors; Vascular endothelial growth factor; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; United States; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0155289

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.