Distribution of DNA Damage Response Inhibitors to the Central Nervous System for Brain Tumor Therapy

Abstract

Brain tumors are associated with a grim prognosis despite the aggressive treatment strategy of surgery, radiation, and chemotherapy. Therefore, there is a need to develop strategies to enhance efficacy of chemo-radiation treatments. DNA damage response (DDR) signaling pathways play a critical role of DNA repair in cancer cells and resistance to radiation and chemotherapy. Inhibition of these pathways can augment tumor kill. Berzosertib, peposertib and AZD1390 are potent small molecule inhibitors of three critical DDR pathways. We evaluated mechanisms limiting central nervous system (CNS) distribution of these molecules and identified their potential for chemo/radiosensitization in brain tumors. CNS distribution of all three molecules is restricted by active efflux mediated by P-gp and/or Bcrp. Moreover, high tissue binding to plasma, brain, and spinal cord, restricts partitioning of unbound drug across the blood-brain barrier (BBB). Additionally, peposertib concentrations in different anatomical regions of the brain were similar, however lower accumulation was observed in the spinal cord. Impact of efflux inhibition using elacridar demonstrated similar increase in peposertib concentrations within each of these regions, indicating that inhibition of efflux activity was functionally similar across these regions. Similarly, no differences were observed in AZD1390 distribution within different anatomical regions of the CNS, and the functional activity of P-gp and Bcrp also remained the same across brain regions. These molecules show heterogeneous tumor distribution in patient-derived xenograft models of brain tumors with drug accumulation maximum within tumor core, slightly lower in adjacent tumor rim, but significantly lower in surrounding normal brain. Berzosertib did not achieve effective chemosensitizing brain and tumor concentrations in vivo. Peposertib, despite its limited CNS delivery, showed potential as a safe yet effective radiosensitizer for brain metastases. Effective radiosensitizing concentrations of AZD1390 were achieved in brain and tumor despite its restricted CNS delivery. Combined, these CNS pharmacokinetic evaluations can guide dosing in pre-clinical efficacy studies and enable future clinical trial design to test these innovative chemo/radiosensitizers with the eventual goal of improving therapy for brain tumors. Integrating knowledge from these studies will aid in determining the potential of DDR inhibitors as effective chemo-radiosensitizing agents in brain tumors.