microRNA therapies for advanced brain tumors

晚期脑肿瘤的 microRNA 疗法

• 批准号: 10580857
• 负责人: Deepak Bhere
• 金额: $ 24.82万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580857
• 关键词: Address; Adjuvant Chemotherapy; Adult; Aftercare; Award; Beds; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cell Line; Cell Proliferation; Cells; Central Nervous System Diseases; Clinical; Data; Development; Diagnosis; Disease; Drug Delivery Systems; Encapsulated; Engineering; Ensure; Epidermal Growth Factor Receptor; Etiology; Excision; Extracellular Matrix; Flow Cytometry; Ganciclovir; Glioblastoma; Goals; Growth; Immune; Immune response; Immune system; Immunity; Implant; In Vitro; Kinetics; Knowledge; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mentors; MicroRNAs; Modeling; Molecular; Mus; Operative Surgical Procedures; Pathway interactions; Patients; Phase; Positron-Emission Tomography; Primary Brain Neoplasms; Prognosis; Proliferating; Proto-Oncogene Proteins c-akt; Publishing; Radiation therapy; Regimen; Resected; Role; STAT3 gene; Safety; Signal Transduction; Simplexvirus; Small RNA; Surgically-Created Resection Cavity; Survival Analysis; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Thymidine Kinase; Time; Treatment Efficacy; Tumor Burden; Tumor Debulking; Tumor Volume; Up-Regulation; Validation; cell growth; chemotherapy; clinical care; clinical translation; effective therapy; exosome; fluorescence imaging; image guided; imaging agent; immune activation; immune clearance; implantation; in vivo; induced pluripotent stem cell; migration; mouse model; neoplastic cell; nerve stem cell; novel; promoter; response; restoration; stem cells; success; suicide gene; synergism; therapeutic miRNA; therapy development; treatment strategy; tumor; tumor microenvironment

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.

摘要 每年有超过14，000名患者被诊断患有胶质母细胞瘤（GBM），这是最恶性的肿瘤形式。 原发性脑肿瘤手术切除后，放射和化疗是治疗选择， GBM，但患者通常死于这种疾病。microRNA（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，从诱导多能干细胞中脱落的外泌体具有很大的前景。 表达miR-124的细胞衍生的神经干细胞（iNSC）靶向脑肿瘤。在辅导（K99） 在本研究的第一阶段，我将评估局部递送到肿瘤中的miR-124介导的免疫效应 通过包被的神经干细胞在肿瘤减积后形成床。我们假设miR-124的调节是通过 来自NSC的富含miR-124的外泌体，当递送到肿瘤切除腔中时，将靶向肿瘤细胞 增殖并增强T细胞介导的GBM细胞的免疫清除。一旦这些效果得到验证， 该奖项的R 00阶段，miR-7和miR-124的调节之间的潜在协同作用， 将分别研究AKT和STAT 3以开发sECM包封的iNSC递送的miR-7/ miR-124 靶向切除的GBM的治疗方法。为了确保iNSC植入的安全性， 病毒-胸苷激酶自杀基因系统将被并入。iNSC-miR-7/miR-124/HSV-TK的功效 将在GBM切除的小鼠模型中进行评价。我们假设miR-124和miR-124的双重调节可能与miR-124的表达有关。 7将靶向对肿瘤细胞生长至关重要的AKT-STAT 3信号传导，并与宿主细胞的活化一起， 免疫系统介导的肿瘤清除将带来治疗益处。经过验证，这种microRNA 的治疗策略将为急需的靶向GBM的新治疗铺平道路。