The ability of glioblastomas to proliferate in an uncontrollable manner and disperse widely within normal brain define the malignant phenotype and make this disease uniformly lethal. We have identified an enzyme that is essential for both glioblastoma invasion and proliferation?Kif11. This enzyme is a molecular motor of the mitotic kinesin family, and is needed both for formation of the mitotic spindle during mitosis as well as for microtubule-based cell motility. Furthermore, it can be inhibited with clinically available drugs that we have shown significantly prolong survival in mouse models of glioblastoma. In this application, we will examine how to optimize the delivery of these drugs to the central nervous system and to identify and overcome the mechanisms tumor cells use to develop resistance to them. Results from these translational studies will be vital to our ongoing efforts at developing Kif11 inhibitors as new and effective therapies for the treatment of glioblastoma.
The ability of glioblastoma to invade brain and proliferate uncontrollably makes this tumor uniformly lethal, and this highlights the need to develop new methods to block brain tumor invasion. In this application, we propose that the mitotic kinesin Kif11 represents such a target, and we will investigate how to optimize therapeutic approaches to inhibit it.
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