Abstract

Effective drug delivery to the brain is critical for the treatment of glioblastoma, an aggressive and invasive primary brain tumor that has a dismal prognosis. Radiation therapy, the mainstay of brain tumor treatment, works by inducing DNA damage. Therefore, inhibiting DNA damage response (DDR) pathways can sensitize tumor cells to radiation and enhance cytotoxicity. AZD1390 is an inhibitor of ataxia-telangiectasia mutated kinase (ATM), a critical regulator of DDR. Our in vivo studies in the mouse indicate that delivery of AZD1390 to the central nervous system (CNS) is restricted due to active efflux by P-gp. The free fraction of AZD1390 in brain and spinal cord were found to be low, thereby reducing the partitioning of free drug to these organs. Co-administration of an efflux inhibitor significantly increased CNS exposure of AZD1390. No differences were observed in distribution of AZD1390 within different anatomical regions of CNS, and the functional activity of P-gp and Bcrp also remained the same across brain regions. In an intracranial glioblastoma patient-derived xenograft (PDX) model, AZD1390 accumulation was higher in the tumor core and rim compared to surrounding brain. Despite this heterogenous delivery within tumor-bearing brain, AZD1390 concentrations in normal brain, tumor rim and tumor core were above in vitro effective radiosensitizing concentrations. These results indicate that despite being a substrate of efflux in the mouse brain, sufficient AZD1390 exposure is anticipated even in regions of normal brain.

Significance Statement Given the invasive nature of GBM, tumor cells are often protected by an intact blood-brain barrier, requiring the development of brain penetrant molecules for effective treatment. We show that efflux mediated by P-gp limits CNS distribution of AZD1390, and there are no distributional differences within anatomical regions of CNS. Despite efflux by P-gp, concentrations effective for potent radiosensitization are achieved in GBM tumor bearing mouse brains indicating that AZD1390 is an attractive molecule for clinical development of brain tumors.