Identifying c-Cbl as a critical point of intervention in glioblastoma multiforme

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DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) remains the most devastating malignancy of the central nervous system, with little progress having been made over the last several decades in terms of therapeutic development. Characterized by pervasive growth, extensive vascularization and marked chemoresistance, GBM exhibits inevitable recurrence and despite treatment, is associated with only a 14-month survival prognosis. Previous work [13] has identified a novel regulatory pathway (the redox/Fyn/c-Cbl (RFC)) pathway that is present in progenitor cells of the CNS, and appears to be dysregulated in GBM. Inhibiting normal regulation of the E3 ubiquitin ligase c-Cbl perpetuates pro-mitogenic signaling through receptor tyrosine kinases (RTKs), and confers resistance against chemotherapeutic agents. Putative involvement in a multitude of intracellular signaling pathways implicates c-Cbl as a potential convergence point in an integrated network mediating GBM pathology. Preliminary data suggest focal adhesion kinase (FAK) and heat shock protein 90 (HSP90) both are contributors to c-Cbl dysfunction, motivating an investigation into pharmacological inhibition of these compounds as a means of rescuing normal c-Cbl regulation. As such, this proposal aims to test the hypotheses that 1) pharmacological inhibition of FAK restores normal c-Cbl function and enables therapeutically relevant targeting of GBM cells 2) pharmacological inhibition of HSP90 also restores normal c-Cbl activity to enable therapeutical targeting of GBM cells and 3) small molecule inhibitors of FAK and HSP90 restore c-Cbl activity and exhibit therapeutic relevance in a human xenograft mouse model of GBM. Genetic knockdown of c-Cbl and perturbation of the RFC pathway in GBM cells will be combined with analysis of protein interactions, cell viability, RTK degradation, and cancer stem cell phenotype in the presence of pharmacological inhibitors and chemotherapeutics to test the importance of c-Cbl function in these effects. Our overarching goal is to identify novel roles for both FAK and HSP90 and confirm the importance of c-Cbl inhibition in glioma biology to guide development of innovative therapeutics.