microRNA therapies for advanced brain tumors

晚期脑肿瘤的 microRNA 疗法

• 批准号: 10818943
• 负责人: Deepak Bhere
• 金额: $ 4.07万
• 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/10818943
• 关键词: Brain Neoplasms; Caring; Cells; Clinical; Data; Development; Diagnosis; Disease; Etiology; Excision; Funding; Glioblastoma; Immune; Immunity; Malignant - descriptor; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Operative Surgical Procedures; Patients; Primary Brain Neoplasms; Proliferating; Radiation therapy; Regimen; Research; Role; Therapeutic; Therapeutic Effect; Validation; chemotherapy; clinical care; combinatorial; immune checkpoint blockade; in vivo; innovation; mouse model; novel; restoration; tumor; tumor heterogeneity; tumor progression

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. Tumor heterogeneity presents a major challenge to development of successful therapies making it increasingly apparent that the use of combination or cocktail therapies would present innovative strategies to tackle GBM. 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. Numerous groups including us have demonstrated the role of microRNA modulation and their therapeutic effects on GBM tumor progression. Our data from the R00 funded research have revealed the critical role of microRNA- 124 restoration and its effect on host immunity in GBM. This in this study, we will evaluate the combinatorial effects of miR-124 modulation with immune checkpoint blockade. The effects of the proposed strategy will be mechanistically evaluated and efficacy will be evaluated using in vivo GBM models. The use of mouse models of GBM tumor resection will mimic clinical scenario of GBM care and further trigger the surgery mediated immune effects on GBM cells. Successful validation of our proposed therapeutic strategy will open avenues for novel treatment options for 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进行放疗和化疗是GBM的治疗选择， 但病人通常会死于这种疾病。肿瘤异质性对发展提出了重大挑战 越来越多的成功疗法使得联合或鸡尾酒疗法的使用变得越来越明显， 提出解决GBM的创新战略。microRNA（miR）正在成为细胞生长的关键调控因子， 分化和增殖;已经涉及多种癌症（包括GBM）的病因学。 包括我们在内的许多研究小组已经证明了microRNA调节的作用及其治疗效果 对GBM肿瘤进展的影响我们从R 00资助的研究中获得的数据揭示了microRNA的关键作用， 124恢复及其对宿主免疫的影响。在这项研究中，我们将评估组合 miR-124调节与免疫检查点阻断的作用。拟议战略的影响将是 将使用体内GBM模型进行机制评价和功效评价。小鼠模型的使用 的GBM肿瘤切除将模拟GBM护理的临床情况，并进一步触发手术介导的免疫反应。 对GBM细胞的影响我们提出的治疗策略的成功验证将为新的 GBM的治疗选择