Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma

Autor:	Rita West, Karen E. Parrish, William F. Elmquist, Alfredo Quinones Hinojosa, Jann N. Sarkaria, Steven S. Rosenfeld, Gautham Gampa, James F. Crish, Rajappa S. Kenchappa, Afroz S. Mohammad, Amanda Luu, Minjee Kim
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	Drug ATP Binding Cassette Transporter Subfamily B media_common.quotation_subject Cell Kinesins lcsh:Medicine Article Mice Cell Line Tumor Tetrahydroisoquinolines medicine Distribution (pharmacology) ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Tumor growth Neoplasm Invasiveness Molecular Targeted Therapy lcsh:Science Mitosis media_common Cancer Cell Proliferation Multidisciplinary business.industry Drug discovery lcsh:R Brain medicine.disease Xenograft Model Antitumor Assays Neoplasm Proteins Disease Models Animal medicine.anatomical_structure Oncology Blood-Brain Barrier Benzamides Cancer research Quinazolines Kinesin Acridines lcsh:Q Efflux business Glioblastoma
Zdroj:	Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020) Scientific Reports
ISSN:	2045-2322
DOI:	10.1038/s41598-020-63494-7
Popis:	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.
Databáze:	OpenAIRE
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