Dynamic Contrast-Enhanced and Diffusion MRI Show Rapid and Dramatic Changes in Tumor Microenvironment in Response to Inhibition of HIF-1α Using PX-478

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.

Navigator respiratory‐triggered diffusion‐weighted imaging in the follow‐up after hepatic radiofrequency ablation—initial results

“…The usefulness of DWI has been demonstrated both in detection and in characterization of focal hepatic lesions (1,3,4). The value of DWI for monitoring the response to different types of tumor treatment is currently being investigated extensively (5)(6)(7)(8)(9).…”

Inhibiting Hypoxia-Inducible Factor 1 for Cancer Therapy

“…Instead, the preclinical development of HIF inhibitors should be guided by evidence in animal models that the target is modulated and that this inhibition is associated with meaningful biological consequences. Several approaches have been used in this regard, ranging from noninvasive imaging of hypoxia response element -dependent expression of bioluminescence (49) to dynamic contrast imaging techniques (50), to assessment of tissue molecular end points relevant to the HIF pathway (e.g., HIF-1a expression assessed by immunohistochenistry, HIF-target genes; refs. 49, 51).…”

A new phantom using polyethylene glycol as an apparent diffusion coefficient standard for MR imaging

“…Second-order coefficients, first-order coefficients, or intercepts of the seven quadratics were plotted on the vertical axis as a function of the PEG concentration (c) on the horizontal axis of the graph. We developed each relational formula (formulas , [1][2], [1][2][3]) based on the sixth-order approximation of the relationship between second-order coefficients, first-order coefficients, or intercepts and PEG concentrations. Using these relational formulas, we created an empirical formula [1] for calculating the ADC values of phantoms made of any PEG concentrations at any measurement temperature.…”

“…We developed each relational formula (formulas [2][3][4]) based on the sixth-order approximation of the relationship between third-order coefficients, secondorder coefficients, first-order coefficients, or intercepts and phantom temperature. Using these relational formulas, we created an empirical formula [2] for calculating PEG concentrations to obtain arbitrary ADC values at any measurement temperature.…”

“…The apparent diffusion coefficient (ADC) map, which is calculated from DWI images and reflects the diffusion of water molecules (1), is available for diagnosis and follow-up after treatment of cerebral infarction (1) or brain tumors (2)(3)(4) and for evaluation of the degree of tumor differentiation (1,5). New pulse sequences, such as diffusion-weighted wholebody imaging with background body signal suppression (DWIBS) (6,7), have been developed.…”