Project 4- Targeting the neuronal microenvironment in gliomas (Monje/Suva)

高级别神经胶质瘤是脑肿瘤相关死亡的主要原因，强调了迫切需要一个 更深入地了解高级别胶质瘤病理生物学和新的治疗途径。我们最近 发现神经元活动强烈促进高级别胶质瘤生长， 称为神经连接素-3是神经胶质瘤生长的重要活性调节机制。活性调节的裂解和 神经胶质瘤生长需要由蛋白酶ADAM 10介导的神经连接素-3从突触的释放， 尽管尚不清楚是什么介导了这种显著的依赖性。此外，我们还发现， 异种移植的神经胶质瘤在体内进化，以在6个月的时间内避开神经连接素-3依赖性。 神经连接素-3缺乏的脑微环境的背景下。在本提案中，我们寻求利用单一 细胞基因组学与患者来源的胶质母细胞瘤原位异种移植物和免疫活性鼠 在神经连接蛋白-3敲除或野生型小鼠中的胶质母细胞瘤同种异体移植物中解剖神经连接蛋白-3信号传导， 完整的神经胶质瘤生态系统使用类似的策略，我们还将揭示一些机制， 异种移植的胶质瘤规避了神经连接素-3依赖性，这一发现不仅将告知神经胶质瘤 相互作用，也是神经胶质瘤进展的基本机制。最后，我们将进行临床前 ADAM 10抑制剂阻断神经连接素-3释放到肿瘤微环境中的有效性和安全性测试 为了提供足够的临床前证据以将这种新的治疗策略用于临床试验， 成人高级别胶质瘤这项未来的试验将补充我们的儿科脑肿瘤联盟赞助的 ADAM 10抑制治疗儿童高级别胶质瘤的I期临床试验。综合考虑， 实验将阐明胶质瘤生长和发展的基本机制，并提出一个新的研究方向。 有希望的新的治疗方法来治疗这些致命的脑癌。

High-grade gliomas are the leading cause of brain tumor-related death, underscoring the urgent need for a deeper understanding of high-grade glioma pathobiology and novel avenues for therapy. We have recently discovered that neuronal activity robustly promotes high-grade glioma growth and that a synaptic molecule called neuroligin-3 is a crucial activity-regulated mechanism for glioma growth. Activity-regulated cleavage and release of neuroligin-3 from synapses, mediated by the protease ADAM10, is required for glioma growth, although it is not yet clear what mediates this striking dependency. Further, we have found that a subset of xenografted gliomas evolve in vivo to circumvent neuroligin-3 dependency over a period of 6 months in the context of a neuroligin-3 deficient brain microenvironment. In the present proposal, we seek to leverage single cell genomics together with patient-derived glioblastoma orthotopic xenografts and immunocompetent murine glioblastoma allografts in neuroligin-3 knockout or wild type mice to dissect neuroligin-3 signaling within the intact glioma ecosystem. Using a similar strategy, we will also uncover the mechanisms by which some xenografted gliomas circumvent neuroligin-3 dependency, findings that will inform not only neuron-glioma interactions but also fundamental mechanisms of glioma progression. Finally, we will perform preclinical efficacy and safety testing of ADAM10 inhibition to block neuroligin-3 release into the tumor microenvironment in an effort to provide sufficient preclinical evidence to bring this novel therapeutic strategy to a clinical trial for adult high-grade gliomas. This future trial will complement our Pediatric Brain Tumor Consortium-sponsored phase 1 clinical trial of ADAM10 inhibition for pediatric high grade glioma. Taken together, the proposed experiments will elucidate fundamental mechanisms of glioma growth and progression and advance a promising new therapeutic approach for these lethal brain cancers.