The ability of malignant gliomas to disperse within normal brain ultimately renders ineffective all of our current therapies for this tumor. This invasive propensity is further stimulated by antiangiogenics, which have entered the mainstream of glioma therapeutics. Unfortunately, treatments designed to block this invasive phenotype do not produce universal or durable response, which underscores the need to find new ways of targeting brain dispersion by this tumor. In our prior work, we established that the molecular motor non-muscle myosin II (NMMII) is an essential component of the glioma invasion apparatus. In this application, we will examine the roles of NMMII in driving glioma invasion and the efficacy of targeting NMMII in blocking the invasive phenotype of malignant gliomas in a set of realistic and robust preclinical models of glioblastoma. Results from these translational studies will be combined with combination therapy studies in our pre-clinical models in order to identify potential synergy between NMMII inhibitors and anti-angiogenic and radiation therapy.

Public Health Relevance

The ability of gliomas to invade brain limits all the current therapies for this disease, and this highlights the need to develop new methods to block brain tumor invasion. In this application, we propose that the molecular motor NMMII represents such a target. In this study, we will critically examine how NMMII drives glioma dispersion and how it can be specifically and effectively targeted.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Fountain, Jane W
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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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

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