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：
10608192
负责人：
CHARLES H COOK
金额：
$ 64.84万
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/10608192
关键词：
Acceleration Address Adjuvant Therapy Affect Antiviral Agents Antiviral Therapy Area Autologous Dendritic Cells Automobile Driving Biology Biometry Blood Vessels Brain Neoplasms CD8-Positive T-Lymphocytes Chemosensitization Clinic Clinical Clinical Treatment Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Data Dedications Diagnosis Disease Future Genes Glioblastoma Goals Growth Herpesviridae 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 T cell infiltration Therapeutic Time Translations Treatment outcome Up-Regulation Valganciclovir Viral Virus Virus Replication YY1 Transcription Factor 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

Acceleration Address Adjuvant Therapy Affect Antiviral Agents Antiviral Therapy Area Autologous Dendritic Cells Automobile Driving Biology Biometry Blood Vessels Brain Neoplasms CD8-Positive T-Lymphocytes Chemosensitization Clinic Clinical Clinical Treatment Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Data Dedications Diagnosis Disease Future Genes Glioblastoma Goals Growth Herpesviridae 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 T cell infiltration Therapeutic Time Translations Treatment outcome Up-Regulation Valganciclovir Viral Virus Virus Replication YY1 Transcription Factor 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

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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.

项目摘要/摘要胶质母细胞瘤（GBM）是一种无法治愈的脑肿瘤，非常需要改善疗法。有每年在美国诊断出的大约10,000例病例，中位生存期约为14个月。证据已经存在近年来，将巨细胞病毒（CMV）与GBM和其他癌症联系起来。但是，角色 GBM中CMV的定义仍然很差。 CMV是人类中普遍的病毒，它居住在一个潜在状态，但可以在某些条件下重新激活。使用潜水员针对CMV的几项临床试验包括免疫疗法和抗病毒药物CMV在内的方法表现出非常承诺的反应 GBM患者，但基本机制尚不清楚。为了提高我们对这一领域的理解在系统性的背景下，开发了一种颅内GBM的免疫能力鼠模型潜在CMV感染。与模拟感染相比，这始终导致生存率明显缩短在多种不同的鼠GBM模型中控制。这些影响可以通过抗病毒治疗来逆转毒品。我们的新初步人类数据显示，CMV血清阳性人类的自由生存降低以及支持小鼠模型相关性的不同表达基因模式的相似性。我们的模型的特征增加了血管形成，血管周周周周周围的积累，CD8+增加了 T细胞浸润和对化学疗法的抗性。我们发现血小板衍生的生长因子δ（PDGFD）通过CMV感染的肿瘤细胞更新，CRISPR介导的PDGFD敲低可防止周细胞招募并严重损害肿瘤的生长。因此，在特定的目标1中，我们将进一步将PDGFD作为潜在的GBM治疗靶标进行研究。另外，我们有具有复制的初步数据 - 有缺陷的病毒突变体表明CMV复制对这种表型至关重要，我们将使用此突变体探索CMV增强肿瘤进展的机制。我们还表明肿瘤微环境受到CMV的显着影响，因此，在特定目的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的重要性效果。在特定目标3中，我们将使用我们的模型研究CMV与标准护理的相互作用化学放疗，就抗病毒药物对疗法的病毒重新激活和敏感性而言。结果拟议的实验将使我们对CMV对GBM的影响有更深入的了解进展，为未来的临床试验提供急需的靶标和合理的治疗组合这种毁灭性的疾病。