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.
Highlights
The five-year survival rate for pancreatic adenocarcinoma (PDAC) is less than 6% and most survivors are those patients with a surgical option.[1,2,3,4,5] the majority of pancreaticPLOS ONE | DOI:10.1371/journal.pone.0155289 May 26, 2016Imaging Biomarkers to Monitor Early Response to Prodrug TH-302Threshold Pharmaceuticals provided support in the form of a salary for author CPH, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript
The kinetic parameters of Dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) to quantify tumor perfusion were estimated on a pixelwise basis by applying the Tofts model as described in [35]
As shown by the histograms, the Ktrans generated from representative Hs766t and Mia-PaCa-2 tumors were dramatically decreased 48 h after TH-302 treatment, as compared to pre-treatment values
Summary
The five-year survival rate for pancreatic adenocarcinoma (PDAC) is less than 6% and most survivors are those patients with a surgical option.[1,2,3,4,5] the majority of pancreaticPLOS ONE | DOI:10.1371/journal.pone.0155289 May 26, 2016Imaging Biomarkers to Monitor Early Response to Prodrug TH-302Threshold Pharmaceuticals provided support in the form of a salary for author CPH, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The five-year survival rate for pancreatic adenocarcinoma (PDAC) is less than 6% and most survivors are those patients with a surgical option.[1,2,3,4,5] the majority of pancreatic. Imaging Biomarkers to Monitor Early Response to Prodrug TH-302. Threshold Pharmaceuticals provided support in the form of a salary for author CPH, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript
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