Abstract 4433: DW-MR imaging as a predictive biomarker of radiosensitization of GBM through targeted inhibition of checkpoint kinases.

Abstract

Abstract Purpose: The inherent treatment resistance of glioblastoma (GBM) can involve multiple mechanisms including checkpoint kinase (Chk1/2) mediated increased DNA repair capability which can attenuate the effects of genotoxic chemotherapies and radiation. The goal of this study was to evaluate DW-MRI as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM. Experimental Design: We evaluated a specific small molecule inhibitor of Chk1/2, AZD7762, in combination with radiation using in vitro human cell lines and in vivo using a genetically engineered GBM mouse model. Diffusion-weighted and T1-contrast MRI were used to follow treatment effects on intracranial tumor cellularity and growth rates, respectively. Results: AZD7762 inhibited clonal proliferation in a panel of GBM cell lines and increased radiosensitivity in p53-mutated GBM cell lines to a greater extent compared to p53-wild type cells. In vivo efficacy of AZD7762 demonstrated a dose-dependent inhibitory effect on GBM tumor growth rate and a reduction in tumor cellularity based on DW-MRI scans along with enhancement of radiation efficacy. Conclusion: DW-MRI was found to be a useful imaging biomarker for the detection of radiosensitization through inhibition of checkpoint kinases. Chk1/2 inhibition resulted in antiproliferative activity, prevention of DNA-damage induced repair, and radiosensitization in preclinical GBM tumor models, both in vitro and in vivo. The effects were found to be maximal in p53-mutated GBM cells. These results provide the rationale for integration of DW-MRI in clinical translation of Chk1/2 inhibition with radiation for the treatment of GBM. Citation Format: Terence Williams, Stefanie Galbán, Fei Li, Kevin Heist, Craig Galbán, Theodore S. Lawrence, Eric C. Holland, Tami Thomae, Thomas Chenevert, Alnawaz Rehemtulla, Brian D. Ross. DW-MR imaging as a predictive biomarker of radiosensitization of GBM through targeted inhibition of checkpoint kinases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4433. doi:10.1158/1538-7445.AM2013-4433