microRNA therapies for advanced brain tumors

晚期脑肿瘤的 microRNA 疗法

基本信息

批准号：
10547976
负责人：
Deepak Bhere
金额：
$ 22.41万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
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/10547976
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 HSV-Tk Gene 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 Proto-Oncogene Proteins c-akt Publishing Radiation therapy Radio Regimen Resected Role STAT3 gene Safety Signal Transduction Simplexvirus Small RNA Surgically-Created Resection Cavity Survival Analysis System T-Lymphocyte Testing Therapeutic Therapeutic Agents Thymidine Kinase Time Treatment Efficacy Tumor Burden Tumor Debulking Tumor Volume Up-Regulation Validation base 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 therapy development treatment strategy tumor tumor microenvironment

项目摘要

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.

抽象的每年有超过 14,000 名患者被诊断患有胶质母细胞瘤 (GBM)，这是最恶性的胶质母细胞瘤形式原发性脑肿瘤的治疗选择是手术切除，然后进行放射和化疗。 GBM，但通常患者死于该疾病，MicroRNA (miR) 正在成为该疾病的关键调节因子。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了诱导多能干脱落的外泌体的巨大前景。细胞衍生的 - 神经干细胞 (iNSC) 表达 miR-124 以靶向脑肿瘤 (K99)。在本研究的阶段，我将评估 miR-124 局部递送到肿瘤中介导的免疫效应我们通过肿瘤减灭后的封装神经干细胞来研究 miR-124 的调节。富含来自 NSC 的 miR-124 的外泌体，当被递送到肿瘤切除腔中时将靶向肿瘤细胞一旦这些效应得到验证，就会促进 GBM 细胞的增殖并增强 T 细胞介导的免疫清除。该奖项的 R00 阶段，miR-7 和 miR-124 的调节之间的潜在协同作用，其目标将分别研究 AKT 和 STAT3 以开发 sECM 封装的 iNSC 传递 miR-7/miR-124 治疗方法为靶向切除GBM，以保证iNSC植入的安全性。病毒-胸苷激酶自杀基因系统将纳入iNSC-miR-7/miR-124/HSV-TK的功效。我们将在 GBM 切除的小鼠模型中对 miR-124 和 miR- 的双重调节进行评估。 7 将靶向对肿瘤细胞生长以及宿主激活至关重要的 AKT-STAT3 信号传导经验证，这种 microRNA 可以通过免疫系统药物清除肿瘤，从而带来治疗益处。基于的治疗策略将为急需的针对 GBM 的新疗法铺平道路。