Defining the role of cytomegalovirus in glioblastoma therapies

定义巨细胞病毒在胶质母细胞瘤治疗中的作用

• 批准号: 10747768
• 负责人: CHARLES H COOK
• 金额: $ 8.93万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-11 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747768
• 关键词: Antiviral Agents; Area; Brain Neoplasms; Clinical Trials; Cytomegalovirus; Cytomegalovirus Infections; Data; Diagnosis; Doctor of Philosophy; Glioblastoma; Goals; Human; Immunocompetent; Immunotherapy; Jasminum; Link; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Mus; Parents; Patient-Focused Outcomes; Patients; Population; Resistance; Role; Therapeutic; Valganciclovir; Virus; blood-brain tumor barrier; design; effective therapy; human model; improved; irradiation; mouse model; response; standard of care; therapy resistant; tumor growth

Summary: Glioblastoma (GBM) is an incurable brain tumor for which improved therapies are badly needed. There are roughly 10,000 cases diagnosed in the US each year, and median survival is ~14 months. Evidence has been accumulating over recent years linking cytomegalovirus (CMV) to GBM and other cancers. However, the role of CMV in GBM remains poorly defined. CMV is a prevalent virus in humans, where it resides lifelong in a latent state but can be reactivated under certain conditions. Several clinical trials targeting CMV using diverse approaches including immunotherapies and the anti-viral drug valganciclovir have shown very promising responses in GBM patients, but the underlying mechanisms are not clear. To improve our understanding of this area we have developed an immunocompetent murine model of intracranial GBM grown in the context of a systemic latent CMV infection. This consistently leads to significantly shortened survival compared with mock infected controls in multiple distinct murine GBM models. These effects can be reversed by treatment with anti- viral drugs. The goal of this study is to investigate the role of cytomegalovirus in therapeutic resistance in glioblastoma, building from our parent RO1 to design new combination approaches. As part of her PhD studies in the lab of Dr Lawler, Jasmine Clark will: 1) Identify anti-viral drugs for the most effective combination with standard of care (chemoirradiation), 2) investigate the role of altered vasculature/blood tumor barriers in therapeutic resistance, and 3) find molecular mechanisms involved in mediating resistance, using our mouse and human models of glioblastoma with CMV. Our goal is to develop improved therapeutic combinations.

概括： 胶质母细胞瘤（GBM）是一种无法治愈的脑肿瘤，迫切需要改进的治疗方法。有 美国每年诊断出大约 10,000 例病例，中位生存期约为 14 个月。证据已 近年来，越来越多的证据表明巨细胞病毒（CMV）与 GBM 和其他癌症有关。然而，角色 GBM 中 CMV 的定义仍然不明确。 CMV 是人类中的一种流行病毒，它终生潜伏在体内。 状态，但可以在某些条件下重新激活。多项针对 CMV 的临床试验使用不同的方法 包括免疫疗法和抗病毒药物缬更昔洛韦在内的方法已显示出非常有希望的 GBM 患者中出现反应，但其潜在机制尚不清楚。为了加深我们对此的理解 我们开发了一种具有免疫功能的颅内 GBM 小鼠模型，该模型是在 全身潜伏巨细胞病毒感染。与模拟相比，这始终导致生存期显着缩短 多个不同的小鼠 GBM 模型中的感染对照。这些影响可以通过抗-治疗来逆转 病毒药物。 本研究的目的是研究巨细胞病毒在胶质母细胞瘤治疗耐药中的作用， 以我们的母公司 RO1 为基础，设计新的组合方法。作为她在博士实验室进行博士学位研究的一部分 Lawler、Jasmine Clark 将： 1) 确定抗病毒药物与标准护理的最有效组合 （化学放疗），2）研究改变的脉管系统/血液肿瘤屏障在治疗抵抗中的作用， 3）利用我们的小鼠和人类模型找到介导耐药性的分子机制 胶质母细胞瘤伴 CMV。我们的目标是开发改进的治疗组合。