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

基本信息

批准号：
10443072
负责人：
CHARLES H COOK
金额：
$ 68.89万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
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/10443072
关键词：
Address Adjuvant Affect Antiviral Agents Antiviral Therapy Area Autologous Dendritic Cells Automobile Driving Biology Biometry Blood Vessels Brain Neoplasms CD8-Positive T-Lymphocytes Cercopithecine Herpesvirus 1 Chemosensitization Clinic Clinical Clinical Treatment Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Data Diagnosis Disease Future Genes Glioblastoma Goals Growth Human Immune Immunity Immunocompetent Immunoglobulin G Immunology Immunotherapy Impairment Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Modeling Molecular Mus Nucleic Acids Operative Surgical Procedures Outcome Patient-Focused Outcomes Patients Pattern Pericytes Phenotype Platelet-Derived Growth Factor Primary Brain Neoplasms Progression-Free Survivals Proteins Publishing Radiation Reporting Research Personnel Resistance Role Sampling Survival Rate Survivors Therapeutic Time Translations Treatment outcome Tumor Immunity Up-Regulation Valganciclovir Viral Virus Virus Replication angiogenesis antiviral immunity blood vessel development chemoradiation chemotherapy cooking defined contribution differential expression experience experimental study human data improved improved outcome in vivo knock-down mouse model mutant neoplastic cell novel novel strategies prevent recruit resistance mechanism response seropositive standard of care temozolomide therapeutic target therapeutically effective transforming virus treatment response treatment strategy tumor tumor growth tumor microenvironment tumor progression

项目摘要

Project Summary/Abstract 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 CMV 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. Our new preliminary human data shows reduced progression free survival in CMV seropositive humans and similarities in patterns of differentially expressed genes supporting the relevance of the mouse model. Our model features increased blood vessel formation, with accumulation of perivascular pericytes, increased CD8+ T cell infiltrates and resistance to chemotherapy. We discovered that platelet-derived growth factor-δ (PDGFD) is upregulated by CMV infection of tumor cells, and that CRISPR-mediated knockdown of PDGFD prevents pericyte recruitment and severely impairs tumor growth. Therefore in Specific Aim 1 we will further investigate PDGFD as a potential GBM therapeutic target. Also, we have preliminary data with a replication- defective viral mutant suggesting that CMV replication is critical to this phenotype, and we will use this mutant to explore the mechanisms by which CMV enhances tumor progression. We also have shown that the tumor microenvironment is significantly impacted by CMV, therefore in Specific Aim 2 we will examine the therapeutic implications of CMV on tumor/immune interactions, and the importance of viral replication in these effects. In Specific Aim 3 we will use our model to investigate the interactions of CMV with standard of care chemoradiation, in terms of viral reactivation and sensitization to therapies by anti-viral drugs. Results from the proposed experiments will bring us to a deeper understanding of the impact that CMV has on GBM progression, providing badly needed targets and rational therapeutic combinations for future clinical trials in this devastating disease.

项目概要/摘要胶质母细胞瘤（GBM）是一种无法治愈的脑肿瘤，迫切需要改进的治疗方法。美国每年诊断出大约 10,000 例病例，中位生存期约为 14 个月。近年来，越来越多的证据表明巨细胞病毒（CMV）与 GBM 和其他癌症之间存在关联。 CMV 在 GBM 中的作用仍不清楚。 CMV 是人类中的一种流行病毒，它终生存在于体内。潜伏状态，但在某些条件下可以重新激活，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 CMV 在内的方法已在以下领域显示出非常有希望的反应： GBM 患者，但其潜在机制尚不清楚，为了提高我们对这一领域的了解。开发了一种免疫活性小鼠颅内 GBM 模型，该模型是在系统性免疫系统的背景下生长的。与模拟感染相比，潜伏的 CMV 感染始终会导致生存期显着缩短。在多个不同的小鼠 GBM 模型中进行对照，这些效应可以通过抗病毒治疗来逆转。我们新的初步人类数据药物显示 CMV 血清阳性人类的无进展生存期降低差异表达基因模式的相似性支持小鼠模型的相关性。模型特征是血管形成增加，血管周围周细胞积累，CD8+增加 T 细胞浸润和化疗耐药。我们发现血小板衍生生长因子-δ (PDGFD)。肿瘤细胞的 CMV 感染上调，并且 CRISPR 介导的 PDGFD 敲低可防止因此，在具体目标 1 中，我们将进一步促进周细胞募集并严重损害肿瘤生长。研究 PDGFD 作为潜在的 GBM 治疗靶点此外，我们还有复制的初步数据。有缺陷的病毒突变体表明 CMV 复制对该表型至关重要，我们将使用该突变体探索 CMV 促进肿瘤进展的机制。微环境受到 CMV 的显着影响，因此在具体目标 2 中，我们将检查 CMV 对肿瘤/免疫相互作用的治疗意义，以及病毒复制在这些相互作用中的重要性在具体目标 3 中，我们将使用我们的模型来研究 CMV 与护理标准的相互作用。放化疗，就病毒再激活和抗病毒药物治疗的敏感性而言。所提出的实验将使我们更深入地了解 CMV 对 GBM 的影响为未来的临床试验提供急需的靶点和合理的治疗组合这种毁灭性的疾病。