Selective Targeting of Glioma Stem Cells Through Sema3C/PlexinD1

 描述（由申请人提供）胶质母细胞瘤是一种无法治愈的原发性脑肿瘤。胶质瘤干细胞（GSC）是一个细胞亚群，抵抗标准治疗，有助于疾病进展。新的GSC特异性靶点的鉴定可以促进新疗法的开发。我们已经发现GSC适合于进化保守的神经发育程序以促进其致瘤性。GSC利用Sema 3C/PlexinD 1来促进GSC的定义特征：存活、自我更新、侵袭和辐射抗性。重要的是，神经祖细胞不使用该途径，这表明抑制Sema 3C/丛蛋白D1将具有高治疗指数。我们现在指导Sema 3C/PlexinD 1的临床翻译进入临床。我们的中心假设是，GSC使用Sema 3C/丛蛋白D1来促进其自身的自我更新，并且Sema 3C/丛蛋白D1充当重要的预后生物标志物和治疗靶标。在目标1中，我们将使用我们的大型GBM标本收集来评估GBM中Sema 3C/丛蛋白D1受体的患病率，并测试Sema 3C在GBM长期和短期存活者中的预后价值。在目标2中，我们将确定Sema 3C/PlexinD 1在调节Wnt/β-catenin信号传导中的作用。在目标3中，我们将提供靶向Sema 3C/丛蛋白D1信号传导轴与放射组合改善胶质母细胞瘤小鼠模型的存活率的原理证明。如果成功，这些发现将导致一项前瞻性临床试验，评估Sema 3C作为预后生物标志物，并指导靶向Sema 3C/PlexinD 1的新型疗法的开发。

 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.