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 distribution 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.