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.
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.
|Lescarbeau, Rebecca S; Lei, Liang; Bakken, Katrina K et al. (2016) Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma. Mol Cancer Ther 15:1332-43|
|Lescarbeau, Rebecca S; Lei, Liang; Bakken, Katrina K et al. (2016) Quantitative phosphoproteomics reveals Wee1 kinase as a therapeutic target in a model of proneural glioblastoma. Mol Cancer Ther :|
|Muretta, Joseph M; Jun, Yonggun; Gross, Steven P et al. (2015) The structural kinetics of switch-1 and the neck linker explain the functions of kinesin-1 and Eg5. Proc Natl Acad Sci U S A 112:E6606-13|
|Venere, Monica; Horbinski, Craig; Crish, James F et al. (2015) The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma. Sci Transl Med 7:304ra143|
|Goulet, Adeline; Major, Jennifer; Jun, Yonggun et al. (2014) Comprehensive structural model of the mechanochemical cycle of a mitotic motor highlights molecular adaptations in the kinesin family. Proc Natl Acad Sci U S A 111:1837-42|
|Sonabend, Adam M; Bansal, Mukesh; Guarnieri, Paolo et al. (2014) The transcriptional regulatory network of proneural glioma determines the genetic alterations selected during tumor progression. Cancer Res 74:1440-51|
|Magri, Laura; Swiss, Victoria A; Jablonska, Beata et al. (2014) E2F1 coregulates cell cycle genes and chromatin components during the transition of oligodendrocyte progenitors from proliferation to differentiation. J Neurosci 34:1481-93|
|Costa, Pedro M; Cardoso, Ana L; NÃ³brega, ClÃ©vio et al. (2013) MicroRNA-21 silencing enhances the cytotoxic effect of the antiangiogenic drug sunitinib in glioblastoma. Hum Mol Genet 22:904-18|
|Yun, Jonathan; Rothrock, Robert J; Canoll, Peter et al. (2013) Convection-enhanced delivery for targeted delivery of antiglioma agents: the translational experience. J Drug Deliv 2013:107573|
|Hopkins, Benjamin D; Fine, Barry; Steinbach, Nicole et al. (2013) A secreted PTEN phosphatase that enters cells to alter signaling and survival. Science 341:399-402|
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