Improving The Delivery Of Novel Molecularly-Targeted Therapies For The Treatment Of Primary And Metastatic Brain Tumors

Abstract

Tumors in the brain are challenging to diagnose and are associated with poor survival outcomes. Brain tumors are difficult to treat, in part, due to restricted drug delivery across the blood-brain barrier (BBB). Although the BBB is compromised in some regions of brain tumors, the degree of disruption is not uniform and certain tumor locations have a functionally intact BBB. A critical component of BBB that restricts entry of therapeutics into brain is active efflux. The objective of this work is to examine brain distribution of novel molecularly-targeted therapies, including evaluation of influence of P-gp and Bcrp-mediated efflux at the BBB, assessment of spatial heterogeneity in drug distribution to brain tumors, and comparison of unbound (active) drug exposures with in vitro efficacy. Ispinesib is a KIF11 inhibitor that inhibits both tumor proliferation and invasion in glioblastoma (GBM). We demonstrate that ispinesib has a limited brain delivery due to efflux by P-gp and Bcrp, and ispinesib delivery is heterogeneous to areas within a tumor in a GBM model. Furthermore, predicted unbound-concentrations in brain were less than in vitro cytotoxic concentrations, suggesting that delivery may limit in vivo efficacy. Also, pharmacological inhibition of efflux transport (elacridar co-administration) improves brain delivery of ispinesib, and future studies will evaluate if enhanced delivery will improve efficacy. CCT196969, LY3009120 and MLN2480 are panRAF inhibitors with minimal paradoxical activation of MAPK pathway and may overcome resistance observed with BRAF inhibitor therapy in melanoma. MEK inhibition is used in combination with BRAF inhibitors to delay resistance. E6201 is a potent MEK inhibitor with a unique macrocyclic structure. While brain distribution of panRAF inhibitors is limited by efflux, E6201 has a favorable brain distribution profile and interacts minimally with P-gp and Bcrp. The delivery of E6201 is variable to regions of tumor in an intracranial melanoma model. However, predicted unbound-concentrations in brain achieve levels higher than in vitro cytotoxic concentrations for LY3009120 and E6201, suggesting possible efficacy in melanoma brain metastases. Future studies evaluating in vivo efficacy in preclinical models will reveal the utility of selected compounds in brain tumor treatment, and if improved delivery translates to superior efficacy.