title: DW-MRI as a Predictive Biomarker of Radiosensitization of GBM through Targeted Inhibition of Checkpoint Kinases.
abstract: OBJECTIVE
  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 diffusion-weighted magnetic resonance imaging (DW-MRI) as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM.
  
  
  METHODS
  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. DW-MRI 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiation Oncology, The Ohio State University, Columbus, OH.
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
authors.forename: Stefanie
authors.initials: S
authors.lastname: Galbán
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Heist
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Galbán
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.forename: Tami L
authors.initials: TL
authors.lastname: Thomae
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Chenevert
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
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