Effective drug delivery to the brain is critical for the treatment of glioblastoma (GBM), 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, 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-glycoprotein (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. Coadministration of an efflux inhibitor significantly increased CNS exposure of AZD1390. No differences were observed in distribution of AZD1390 within different anatomic regions of CNS, and the functional activity of P-gp and breast cancer resistance protein also remained the same across brain regions. In an intracranial GBM patient–derived xenograft model, AZD1390 accumulation was higher in the tumor core and rim compared with 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 glioblastoma (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-glycoprotein (P-gp) limits central nervous system (CNS) distribution of AZD1390 and that 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.
|Number of pages
|Journal of Pharmacology and Experimental Therapeutics
|Published - Oct 1 2022
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health National Cancer Institute [Grant U19-CA264362], [Grant U54-CA210180], [Grant U01-CA227954], and [Grant P50-CA108961] and National Institute of Neurological Disorders and Stroke [Grant R24-NS092940]. S.T. was supported by the Rory P. Remmel and Cheryl L. Zimmerman Fellowship in Drug Metabolism and Pharmacokinetics, Edward G. Rippie Fellowship, Bighley Graduate Fellowship, Ronald J. Sawchuk Fellowship in Pharmacokinetics, and Doctoral Dissertation Fellowship.
© 2022 American Society for Pharmacology and Experimental Therapy. All rights reserved.
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Antineoplastic Agents/pharmacology
- Ataxia Telangiectasia/drug therapy
- Blood-Brain Barrier/metabolism
- Brain Neoplasms/drug therapy
- Glioblastoma/drug therapy
- Neoplasm Proteins/metabolism
- Protein Kinase Inhibitors/metabolism
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural