The effective treatment of brain tumors is a considerable challenge in part because of the presence of the blood-brain barrier (BBB) that limits drug delivery. Glioblastoma multiforme (GBM) is an aggressive and infiltrative primary brain tumor with an extremely poor prognosis after standard-of-care therapy with surgery, radiotherapy (RT), and chemotherapy. DNA damage response (DDR) pathways play a critical role in DNA repair in cancer cells, and inhibition of these pathways can potentially augment RT and chemotherapy tumor cell toxicity. The ataxia telangiectasia and Rad3-related protein (ATR) kinase is a key regulator of the DDR network and is potently and selectively inhibited by the ATR inhibitor berzosertib. Although in vitro studies demonstrate a synergistic effect of berzosertib in combination with temozolomide, in vivo efficacy studies have yet to recapitulate this observation using intracranial tumor models. In the current study, we demonstrate that delivery of berzosertib to the brain is restricted by efflux at the BBB. Berzosertib has a high binding affinity to brain tissue compared with plasma, thereby leading to low free drug concentrations in the brain. Berzosertib dis-tribution is heterogenous within the tumor, wherein concentrations are substantially lower in normal brain and invasive tumor rim (wherein the BBB is intact) when compared with those in the tumor core (wherein the BBB is leaky). These results demonstrate that high tissue binding and limited and heterogenous brain distribution of berzosertib may be important factors that influence the efficacy of berzosertib therapy in GBM. SIGNIFICANCE STATEMENT This study examined the brain delivery and efficacy of berzosertib in patient-derived xenograft models of glioblastoma multiforme (GBM). Berzosertib is actively effluxed at the blood-brain barrier and is highly bound to brain tissue, leading to low free drug concentrations in the brain. Berzosertib is heterogeneously distributed into different regions of the brain and tumor and, in this study, was not efficacious in vivo when combined with temozolomide. These factors inform the future clinical utility of berzosertib for GBM.
|Original language||English (US)|
|Number of pages||15|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Dec 1 2021|
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health National Cancer Institute [Grants RO1 CA138437, RO1 NS077921, U54 CA210180, U01 CA227954, and P50 CA108960]. 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.
Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't