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• W1971011955 abstract "BACKGROUND: Two of the defining features of glioblastoma are their ability to invade brain and to proliferate. While both processes are stimulated by the multiple signaling cascades that are activated in GBM, the redundancy present in these pathways has limited the clinical efficacy of kinase inhibitors. An alternative would be to directly target the cellular machinery that drives dispersion and proliferation. This machinery includes “molecular motors”—a superfamily of enzymes that generate the forces needed for a wide variety of cellular physiologies. In this study, we have examined two members from this family that can be targeted with clinically available drugs—cytoplasmic myosin II, which drives cellular motility, and Eg5, which drives the separation of the chromosomes during mitosis. METHODS: Rodent proneural glioblastomas were generated by intracranial injection of PDGF-expressing bi-cistronic retroviruses, and tumor cell invasion in vitro and ex vivo was examined as described (Ivkovic et al., Mol. Biol. Cell, 23, 533-42; Isermann et al., Curr. Protoc. Cell Biol., 2012). Patient-derived human glioma stem cells (GSCs) were isolated and maintained as described (Cheng et al., Cell, 153, 139-52). RESULTS: Myosin II: Myosin II isoforms are upregulated in all four subtypes of GBM, and expression correlates inversely with survival. We find that PDGF abolishes the anti-invasive effect of the EGFR inhibitior erlotinib on EGF-stimulated tumor dispersion, and, likewise, EGF abolishes the corresponding effect of the PDGFRα inhibitor imatinib on PDGF-stimulated tumor migration. However, blebbistatin, an allosteric inhibitor of myosin II, effectively blocks glioma dispersion even with simultaneous activation of both pathways. Furthermore, the rho kinase inhibitor fasudil, which inhibits myosin II and is used clinically for the treatment of pulmonary hypertension, also blocks PDGF-stimulated tumor invasion. Eg5: We find that Eg5 is consistently overexpressed in GSCs, compared to non-GSCs and that GSCs exhibit a greater sensitivity to ispinesib, a clinically available Eg5 inhibitor, compared to non-GSCs. Eg5 inhibition compromises the tumor initiation capability of GSCs as well as tumor progression in an orthotopic xenograft model. CONCLUSIONS: Prior efforts to block glioma invasion and proliferation have been hampered both by therapy-resistant GSCs and the redundancy present in pro-migratory signaling cascades. Our results indicate that molecular motors represent a set of targets whose inhibition blocks glioma dispersion and proliferation regardless of the activity of upstream growth and dispersion-promoting pathways and they imply that further pre-clinical and clinical development of molecular motor inhibitors in malignant glioma is warranted. SECONDARY CATEGORY: Preclinical Experimental Therapeutics." @default.
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• W1971011955 date "2014-07-01" @default.
• W1971011955 modified "2023-09-26" @default.
• W1971011955 title "MOLECULAR MOTORS AS NOVEL TARGETS TO BLOCK GLIOMA DISPERSION AND PROLIFERATION" @default.
• W1971011955 doi "https://doi.org/10.1093/neuonc/nou206.66" @default.
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