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/?-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.
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.
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| Man, Jianghong; Yu, Xingjiang; Huang, Haidong et al. (2018) Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-like Cells. Cell Stem Cell 22:104-118.e6 |
| Zhou, Wenchao; Chen, Cong; Shi, Yu et al. (2017) Targeting Glioma Stem Cell-Derived Pericytes Disrupts the Blood-Tumor Barrier and Improves Chemotherapeutic Efficacy. Cell Stem Cell 21:591-603.e4 |
