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.
Bibliographical noteFunding Information:
The authors thank James Fisher, Clinical Pharmacology Analytical Laboratory, University of Minnesota, for his support in the development of the LC-MS/MS assays. This work was supported by the National Institutes of Health grants R01-NS073610 (to SSR and WFE), U54-CA210180 (to JNS and WFE) and U54-CA210190 (to SSR). Gautham Gampa was supported by the Ronald J. Sawchuk Fellowship in Pharmacokinetics and University of Minnesota Doctoral Dissertation Fellowship.
© 2020, The Author(s).
- ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors
- ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors
- Blood-Brain Barrier/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Disease Models, Animal
- Kinesin/antagonists & inhibitors
- Molecular Targeted Therapy
- Neoplasm Invasiveness/genetics
- Neoplasm Proteins/antagonists & inhibitors
- Xenograft Model Antitumor Assays
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural