Abstract

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.

Public Health Relevance

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073610-07
Application #
9566311
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fountain, Jane W
Project Start
2017-07-01
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224

  Publications

Juliano, Joseph; Gil, Orlando; Hawkins-Daarud, Andrea et al. (2018) Comparative dynamics of microglial and glioma cell motility at the infiltrative margin of brain tumours. J R Soc Interface 15:
Laramy, Janice K; Kim, Minjee; Parrish, Karen E et al. (2018) Pharmacokinetic Assessment of Cooperative Efflux of the Multitargeted Kinase Inhibitor Ponatinib Across the Blood-Brain Barrier. J Pharmacol Exp Ther 365:249-261
Prahl, Louis S; Bangasser, Patrick F; Stopfer, Lauren E et al. (2018) Microtubule-Based Control of Motor-Clutch System Mechanics in Glioma Cell Migration. Cell Rep 25:2591-2604.e8
Muretta, Joseph M; Reddy, Babu J N; Scarabelli, Guido et al. (2018) A posttranslational modification of the mitotic kinesin Eg5 that enhances its mechanochemical coupling and alters its mitotic function. Proc Natl Acad Sci U S A 115:E1779-E1788
Kizilbash, Sani H; Gupta, Shiv K; Chang, Kenneth et al. (2017) Restricted Delivery of Talazoparib Across the Blood-Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma. Mol Cancer Ther 16:2735-2746
Laramy, Janice K; Kim, Minjee; Gupta, Shiv K et al. (2017) Heterogeneous Binding and Central Nervous System Distribution of the Multitargeted Kinase Inhibitor Ponatinib Restrict Orthotopic Efficacy in a Patient-Derived Xenograft Model of Glioblastoma. J Pharmacol Exp Ther 363:136-147
Klank, Rebecca L; Decker Grunke, Stacy A; Bangasser, Benjamin L et al. (2017) Biphasic Dependence of Glioma Survival and Cell Migration on CD44 Expression Level. Cell Rep 18:23-31
Karpel-Massler, Georg; Ishida, Chiaki Tsuge; Bianchetti, Elena et al. (2017) Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nat Commun 8:1067
Atherton, Joseph; Yu, I-Mei; Cook, Alexander et al. (2017) The divergent mitotic kinesin MKLP2 exhibits atypical structure and mechanochemistry. Elife 6:
Wrzeszczynski, Kazimierz O; Frank, Mayu O; Koyama, Takahiko et al. (2017) Comparing sequencing assays and human-machine analyses in actionable genomics for glioblastoma. Neurol Genet 3:e164

Showing the most recent 10 out of 30 publications