microRNA therapies for advanced brain tumors

摘要 每年有超过14,000名患者被诊断为胶质母细胞瘤(GBM)，这是 原发脑瘤。手术切除，然后放、化疗是治疗方案。 GBM，但患者通常会死于这种疾病。MicroRNAs(MiR)正在成为 细胞分化和增殖；与多种癌症的病因学有关，包括 GBM。我们令人兴奋的初步研究显示，从诱导的多能干细胞中脱落的外切体有很大的希望 表达miR-124的细胞源性神经干细胞(INSC)靶向脑肿瘤。《被导师》(K99) 在本研究阶段，我将评估局部注射miR-124对肿瘤的免疫效果 肿瘤摘除后，通过包裹的神经干细胞进行卧床。我们假设miR-124通过 富含来自神经干细胞的miR-124的外切体送入肿瘤切除腔后将靶向肿瘤细胞 促进T细胞对GBM细胞的免疫清除。一旦这些效果得到验证，就会在 该奖项的R00阶段，miR-7和miR-124的调制之间的潜在协同作用，其目标是 将分别研究AKT和STAT3，以开发SECM封装的iNSC递送miR-7/miR-124 靶向切除基底膜的治疗途径。为了确保iNSC植入的安全性，单纯疱疹病毒 病毒-胸苷激酶自杀基因系统将被纳入。INSC-miR-7/miR-124/HSV-TK的疗效观察 将在小鼠的基底膜切除模型中进行评估。我们假设miR-124和miR-124的双重调制 7将针对对肿瘤细胞生长至关重要的AKT-STAT3信号，并与宿主的激活一起 免疫系统药物清除肿瘤将带来治疗益处。经过验证，这种微RNA 以此为基础的治疗策略将为靶向GBM的急需的新疗法铺平道路。

ABSTRACT Each year upwards of 14,000 patients are diagnosed with Glioblastoma (GBM), the most malignant form of primary brain tumor. Surgical resection followed by radio and chemotherapies are the treatment options for GBM, but patients generally succumb to the disease. MicroRNAs (miR) are emerging as key regulators of cellular differentiation and proliferation; have been implicated in the etiology of a variety of cancers, including GBM. Our exciting preliminary studies show great promise for exosomes shed from induced pluripotent stem cell derived - neural stem cells (iNSC) expressing miR-124 to target brain tumors. In the mentored (K99) phase of this study, I will evaluate the immune effects mediated by miR-124 delivered locally into the tumor bed via encapsulated neural stem cells following tumor debulking. We hypothesize that miR-124 modulation by exosomes enriched in miR-124 from NSC, when delivered into the tumor resection cavity will target tumor cell proliferation and enhance T-cell mediated immune clearance of GBM cells. Once these effects are validated, in the R00 phase of the award, the potential synergy between the modulation of miR-7 and miR-124, which target AKT and STAT3 respectively will be studied to develop a sECM encapsulated iNSC delivered miR-7/ miR-124 therapeutic approach to target resected GBM. In order to ensure safety of iNSC implantation, the herpes simplex virus – thymidine kinase suicide gene system will be incorporated. The efficacy of iNSC-miR-7/miR-124/HSV-TK will be evaluated in mouse models of GBM resection. We hypothesize that dual modulation of miR-124 and miR- 7 will target the AKT-STAT3 signaling that is critical to tumor cell growth and together with the activation of host immune system medicated tumor clearance will present therapeutic benefit. Upon validation, this microRNA based therapeutic strategies will pave path to much needed novel treatments to target GBM.