MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity

Abstract

Background:The phosphoinositide-3 kinase (PI3K) pathway is an attractive therapeutic target. However, difficulty in predicting therapeutic response limits the clinical implementation of PI3K inhibitors. This study evaluates the utility of clinically relevant magnetic resonance imaging (MRI) biomarkers for noninvasively assessing the in vivo response to the dual PI3K/mTOR inhibitor BEZ235 in two ovarian cancer models with differential PI3K pathway activity.Methods:The PI3K signalling activity of TOV-21G and TOV-112D human ovarian cancer cells was investigated in vitro. Cellular and vascular response of the xenografts to BEZ235 treatment (65 mg kg−1, 3 days) was assessed in vivo using diffusion-weighted (DW) and dynamic contrast-enhanced (DCE)-MRI. Micro-computed tomography was performed to investigate changes in vascular morphology.Results:The TOV-21G cells showed higher PI3K signalling activity than TOV-112D cells in vitro and in vivo. Treated TOV-21G xenografts decreased in volume and DW-MRI revealed an increased water diffusivity that was not found in TOV-112D xenografts. Treatment-induced improvement in vascular functionality was detected with DCE-MRI in both models. Changes in vascular morphology were not found.Conclusions:Our results suggest that DW- and DCE-MRI can detect cellular and vascular response to PI3K/mTOR inhibition in vivo. However, only DW-MRI could discriminate between a strong and weak response to BEZ235.

Multiparametric characterization of response to anti‐angiogenic therapy using USPIO contrast‐enhanced MRI in combination with dynamic contrast‐enhanced MRI

“…21 Only voxels with at least 50% enhancement after 1 min were considered. 21 Only voxels with at least 50% enhancement after 1 min were considered.…”

Targeted Inhibition of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Sensitizes Pancreatic Cancer Cells to Doxorubicin without Exacerbating Cardiac Toxicity

“…Inhibition with BEZ has effects on several downstream effectors, including AKT, ribosomal protein S6 (S6), and the translation initiation factor 4E binding protein 1. It has previously been tested for use in hepatocellular carcinoma, multiple myeloma, and other cancers that commonly have mutations or increased gene expression that lead to overactivation of the PI3K pathway (Baumann et al, 2009;McMillin et al, 2009;Kirstein et al, 2013;Cebulla et al, 2015). BEZ has also been shown to have beneficial effects in combination with cytotoxic agents, including DOX (Manara et al, 2010;Schult et al, 2012;Westhoff et al, 2013).…”

Pharmacodynamic Biomarker Development for PI3K Pathway Therapeutics

“…117,118 Both DW-MRI and DCE-MRI have been proposed as tools for measuring response to PI3K pathway inhibitors and have been evaluated in preclinical in vivo models. [119][120][121] In a recent study, ADC was found to be a useful biomarker for response to the dual PI3K-mTOR inhibitor BEZ235 in an ovarian cancer xenograft model. 119 In the same study, DCE-MRI, which provides information on tumor perfusion and vascular permeability also proved to be a useful biomarker for response.…”

“…[119][120][121] In a recent study, ADC was found to be a useful biomarker for response to the dual PI3K-mTOR inhibitor BEZ235 in an ovarian cancer xenograft model. 119 In the same study, DCE-MRI, which provides information on tumor perfusion and vascular permeability also proved to be a useful biomarker for response. The parameter v e is a measure of the extravascular extracellular space and, similar to ADC, may be related to the cellular density of the tumor tissue.…”