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Selective Targeting of Glioma Stem Cells Through Sema3C/PlexinD1

通过 Sema3C/PlexinD1 选择性靶向神经胶质瘤干细胞

基本信息

批准号：
9900879
负责人：
Jennifer S Yu
金额：
$ 34.67万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900879
关键词：
Animals Apoptosis Binding Biological Assay Biological Markers Cancer Control Cell Survival Cells Clinic Clinical Clinical Trials Complex Data Development Disease Progression Genes Genetically Engineered Mouse Glioblastoma Glioma Goals Human Knockout Mice Long-Term Survivors Mediator of activation protein Modeling NRP1 gene Oncogenic Pathway interactions Population Positioning Attribute Prevalence Primary Brain Neoplasms Prognostic Marker Proteins Radiation Radiation Oncologist Radiation therapy Recurrence Regulation Reporter Reporting Resistance Role Sampling Series Signal Transduction Specimen Survivors Testing Therapeutic Therapeutic Index Transactivation Translations Tumor Bank Tumorigenicity WNT Signaling Pathway Xenograft Model axon guidance base beta catenin clinical translation improved knock-down man mouse model mutant nerve stem cell nestin protein new therapeutic target novel novel therapeutics overexpression patient subsets prognostic prognostic assays prognostic value programs prospective protein expression public health relevance radiation resistance radioresistant receptor sample collection self-renewal small hairpin RNA stem cells therapeutic target tumor tumor growth tumor progression

项目摘要

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.

说明(申请人提供)胶质母细胞瘤是一种无法治愈的原发脑肿瘤。胶质瘤干细胞(GSCs)是抵抗标准治疗而导致疾病进展的一种细胞亚群。识别新的GSC特异性靶点可能有助于开发新的治疗方法。我们发现，GSCs适合一种进化保守的神经发育程序来促进它们的致瘤性。GSCs利用Sema3C/PlexinD1来促进GSCs的定义特征：存活、自我更新、侵袭和辐射抵抗。重要的是，神经前体细胞不使用这一途径，这表明抑制Sema3C/PlexinD1将具有较高的治疗指数。我们现在指导Sema3C/PlexinD1的临床翻译进入临床。我们的中心假设是GSC使用Sema3C/PlexinD1促进自身的自我更新，Sema3C/PlexinD1是重要的预后生物标志物和治疗靶点。在目标1中，我们将使用我们收集的大量GBM标本来评估Sema3C/PlexinD1受体在GBM中的患病率，并测试Sema3C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Sema3C/PlexinD1在调节Wnt/β-catenin信号转导中的作用。在目标3中，我们将提供针对Sema3C/PlexinD1信号轴的靶向与放射相结合提高胶质母细胞瘤小鼠模型存活率的原理证明。如果成功，这些发现将导致一项评估Sema3C作为预后生物标志物的前瞻性临床试验，并指导针对Sema3C/PlexinD1的新疗法的开发。