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Updated: Aug 17, 2026
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to
Bénédicte F Jordan1, Matthew Runquist, Natarajan Raghunand
1Department of Biochemistry, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
Abstract:
PX-478 is a new agent known to inhibit the hypoxia-responsive transcription factor, HIF-1alpha, in experimental tumors. The current study was undertaken in preparation for clinical trials to determine which noninvasive imaging endpoint(s) is sensitive to this drug's actions. Dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) were used to monitor acute effects on tumor hemodynamics and cellularity, respectively. Mice bearing human xenografts were treated either with PX-478 or vehicle, and imaged over time. DW imaging was performed at three b values to generate apparent diffusion coefficient of water (ADCw) maps. For DCE-MRI, a macromolecular contrast reagent, BSA-Gd-DTPA, was used to determine vascular permeability and vascular volume fractions. PX-478 induced a dramatic reduction in tumor blood vessel permeability within 2 hours after treatment, which returned to baseline by 48 hours. The anti-VEGF antibody, Avastin, reduced both the permeability and vascular volume. PX-478 had no effect on the perfusion behavior of a drug-resistant tumor system, A-549. Tumor cellularity, estimated from ADCw, was significantly decreased 24 and 36 hours after treatment. This is the earliest significant response of ADC to therapy yet reported. Based on these preclinical findings, both of these imaging endpoints will be included in the clinical trial of PX-478.
Insights
PX-478 significantly reduces tumor blood vessel permeability and increases cellularity, as shown by MRI. These findings support its use in upcoming clinical trials for cancer treatment.
Area of Science:
- Oncology
- Medical Imaging
- Pharmacology
Background:
- Hypoxia-inducible factor 1-alpha (HIF-1alpha) is a key regulator in tumor response to hypoxia.
- PX-478 is an experimental agent targeting HIF-1alpha in tumors.
- Noninvasive imaging is crucial for evaluating therapeutic responses in preclinical and clinical settings.
Purpose of the Study:
- To identify sensitive noninvasive imaging endpoints for PX-478's effects.
- To assess the acute impact of PX-478 on tumor hemodynamics and cellularity using MRI.
- To guide the selection of imaging biomarkers for future clinical trials.
Main Methods:
- Dynamic Contrast-Enhanced (DCE) MRI to evaluate tumor vascular permeability and volume.
- Diffusion-Weighted (DW) MRI to assess tumor cellularity via apparent diffusion coefficient of water (ADCw).
- Treatment of human xenografts in mice with PX-478 or vehicle, followed by serial MRI.
Main Results:
- PX-478 rapidly decreased tumor vascular permeability within 2 hours, returning to baseline by 48 hours.
- Tumor cellularity, measured by ADCw, showed a significant decrease at 24 and 36 hours post-treatment.
- PX-478 did not affect perfusion in the drug-resistant A-549 tumor model.
Conclusions:
- DCE-MRI and DW-MRI are sensitive to PX-478's acute effects on tumor vasculature and cellularity.
- The observed changes in ADCw represent the earliest significant response to therapy reported to date.
- Both imaging modalities will be incorporated into the clinical trial of PX-478.
