Abstract
Glioblastoma, the most lethal primary brain cancer, is extremely proliferative and invasive. Tumor cells at tumor/brain-interface often exist behind a functionally intact blood-brain barrier (BBB), and so are shielded from exposure to therapeutic drug concentrations. An ideal glioblastoma treatment needs to engage targets that drive proliferation as well as invasion, with brain penetrant therapies. One such target is the mitotic kinesin KIF11, which can be inhibited with ispinesib, a potent molecularly-targeted drug. Although, achieving durable brain exposures of ispinesib is critical for adequate tumor cell engagement during mitosis, when tumor cells are vulnerable, for efficacy. Our results demonstrate that the delivery of ispinesib is restricted by P-gp and Bcrp efflux at BBB. Thereby, ispinesib distribution is heterogeneous with concentrations substantially lower in invasive tumor rim (intact BBB) compared to glioblastoma core (disrupted BBB). We further find that elacridar—a P-gp and Bcrp inhibitor—improves brain accumulation of ispinesib, resulting in remarkably reduced tumor growth and extended survival in a rodent model of glioblastoma. Such observations show the benefits and feasibility of pairing a potentially ideal treatment with a compound that improves its brain accumulation, and supports use of this strategy in clinical exploration of cell cycle-targeting therapies in brain cancers.
Highlights
Glioblastoma (GBM), the most common and lethal of primary brain tumors, has two defining phenotypes: uncontrollable proliferation and diffuse infiltration within the brain[1,2,3,4,5,6]
It seems highly unlikely that any appreciable fraction of cells from a tumor with a low proliferative index will be affected by a drug that is only active in M phase, if the drug has a short half-life and can only be dosed intermittently
Ispinesib was administered intravenously to Friend leukemia virus strain B (FVB) wild-type mice and to FVB mice deleted for the P-gp and breast cancer resistance protein (Bcrp) efflux transporters in order to determine how these efflux transporters affect brain distribution
Summary
Glioblastoma (GBM), the most common and lethal of primary brain tumors, has two defining phenotypes: uncontrollable proliferation and diffuse infiltration within the brain[1,2,3,4,5,6]. MTs are essential for peripheral and central nervous system (PNS, CNS) function, and dose-limiting neurotoxicity has been observed with these MT-targeting drugs[8,9] This has served as an impetus for developing drugs that target other components of mitotic spindle. Over the last twenty years, more than 50 highly specific and potent small-molecule inhibitors of KIF11 have been developed[10] While these drugs are not neurotoxic[14,15,16,17], they have been disappointing as anti-cancer therapeutics. Ispinesib (SB-715992) (Supplementary Fig. S1) is a potent and highly specific KIF11 inhibitor, and we have shown that it is active against GBM cells, including treatment resistant TICs, in vitro and against orthotopic GBM models in vivo[7]. Our results support the use of targeting efflux mechanisms as an adjunct to therapeutic development of GBM therapies
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