Abstract
BACKGROUND: Advanced imaging techniques have been proposed as potentially useful tools for evaluation of biological effects of new targeted agents. CTO is an oral inhibitor of non-voltage-dependent calcium signaling that modulates several pathways, including EGFR, MEK, RAS, HDAC, HSP90, WNT/B-catenin, Akt, ERK, VEGF and Bcr-Abl. We prospectively evaluated advanced MRI parameters in a phase I trial of combined CTO and adjuvant temozolomide for temozolomide-refractory recurrent/progressive malignant glioma, aiming at characterizing early pharmacodynamic effects after drug exposure. METHODS: Within an exploratory imaging correlative study, a subset of patients enrolled in this trial underwent DCE-MRI and DWI at baseline and after two 28-day cycles. Changes in imaging parameters were evaluated utilizing volumetric histogram analysis of the entire tumor (NordicICE v2.3; NordicNeuroLab, Bergen, Norway), including blood perfusion (relative plasma volume [Vp]), vascular permeability (Ktrans) and diffusion (apparent diffusion coefficient [ADC]). Normalized results were analyzed with Mann-Whitney u tests. RESULTS: Among 17 enrolled patients, 7 were included in the imaging component (glioblastoma: 5; grade III: 2; MGMT methylated: 3, unmethylated: 2, unknown: 2; bevacizumab failures: 3), with CTO dose range of 219-625mg/m2/day. All patients displayed a reduction in blood perfusion, with mean Vp = 10.65 at baseline vs 3.82 after 2 cycles, p = 0.001. There were no statistically significant differences in vascular permeability parameters, such as Ktrans (mean 11.07 vs 5.14, p = 0.38) or ADC (mean 1.54 vs 1.54, p = 0.81). CONCLUSIONS: DCE-MRI depicted decreases in blood perfusion, demonstrating biological effects of CTO in all evaluated patients after two cycles. Interestingly, such changes were not accompanied by significant decreases in vascular permeability, suggesting an effect distinct from that observed with bevacizumab and VEGF blockade, and likely reflecting modulation of other signaling pathways. This study provides insight into the mechanism of action of CTO, and highlights the usefulness of advanced neuroimaging in early drug development in brain tumors.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
