DESCRIPTION (provided by applicant) Glioblastoma is an incurable primary brain tumor. Glioma stem cells (GSCs) are a subpopulation of cells that resist standard therapy to contribute to disease progression. Identification of new GSC-specific targets may facilitate the development of novel therapeutics. We have found that GSCs appropriate an evolutionary conserved neurodevelopmental program to promote their tumorigenicity. GSCs utilize Sema3C/PlexinD1 to promote the defining features of GSCs: survival, self-renewal, invasion and radioresistance. Importantly, neural progenitor cells do not use this pathway, suggesting that inhibition of Sema3C/PlexinD1 will have a high therapeutic index. We now guide the clinical translation of Sema3C/PlexinD1 into the clinic. Our central hypothesis is that GSCs use Sema3C/PlexinD1 to promote their own self- renewal and that Sema3C/PlexinD1 serve as important prognostic biomarkers and therapeutic targets. In Aim 1, we will use our large GBM specimen collection to assess the prevalence of Sema3C/PlexinD1 receptor in GBM and test the prognostic value of Sema3C in long and short-term survivors of GBM. In Aim 2, we will determine the role of Sema3C/PlexinD1 in regulating Wnt/β-catenin signaling. In Aim 3, we will provide proof- of-principle that targeting the Sema3C/PlexinD1 signaling axis in combination with radiation improves survival in mouse models of glioblastoma. If successful, these findings will lead to a prospective clinical trial assessing Sema3C as a prognostic biomarker and guide the development of novel therapeutics targeting Sema3C/PlexinD1.

PUBLIC HEALTH RELEVANCE: Efficient targeting of glioma stem cells is needed to provide durable cancer control. We have identified a neurodevelopmental pathway that is selectively used by glioma stem cells but not neural progenitor cells to drive cancer progression. Therefore, targeting this pathway may have a high therapeutic index. If successful, the findings of this study will guide the clinical translation of this pathway in glioblastoma prognostication and therapy.