The Role of Cidofovir and Structural Analogs as Adjuvant Therapy for Glioblastoma

西多福韦和结构类似物作为胶质母细胞瘤辅助治疗的作用

• 批准号: 9135258
• 负责人: CHARLES S COBBS
• 金额: $ 55.05万
• 依托单位: SWEDISH MEDICAL CENTER, FIRST HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-04 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135258
• 关键词: Address; Adjuvant Therapy; Adverse reactions; Animals; Antitumor Response; Antiviral Agents; Antiviral Therapy; Apoptosis; Apoptotic; Automobile Driving; Biological Availability; Brain; Brain Neoplasms; Cell Culture Techniques; Cell Line; Cells; Cidofovir; Critical Pathways; Cytomegalovirus; Cytomegalovirus Infections; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Diagnosis; Disease; Drug Kinetics; Drug effect disorder; Exhibits; FDA approved; Genetically Engineered Mouse; Genomic DNA; Glioblastoma; Glioma; Growth; Health; Human; Immune response; Immune system; In Vitro; Inflammatory; Investigation; Ionizing radiation; Knowledge; Laboratories; MGMT gene; Mediating; Modality; Molecular Mechanisms of Action; Mus; Newly Diagnosed; Normal Cell; Pathway interactions; Patients; Penetration; Phenotype; Prevention; Primary Brain Neoplasms; Property; Radiation; Radiation therapy; Radiolabeled; Recovery; Recurrence; Regimen; Regulation; Research Personnel; Resistance; Role; Source; Stem cells; Testing; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Transgenic Mice; Tumor Suppressor Genes; Viral Proteins; Xenograft Model; Xenograft procedure; analog; antitumor effect; base; cancer therapy; cell growth; cytosine analog; cytotoxic; design; dosage; gene product; human disease; improved; improved outcome; in vivo; inhibitor/antagonist; molecular subtypes; mouse model; neoplastic cell; nephrotoxicity; novel; novel therapeutics; prevent; professor; promoter; radiotracer; response; standard of care; temozolomide; tumor; tumor DNA; tumor microenvironment; tumor progression; uptake

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is a fatal primary brain tumor, with most patients surviving 12-15 months following diagnosis, despite receiving standard of care treatment. We discovered that human cytomegalovirus (HCMV) is present in a high percentage of GBM, and these findings have been confirmed by multiple groups. Our co- investigator, Dr. Nino Chiocca, has recently demonstrated that CMV infection accelerates tumor progression to GBM in a transgenic mouse model of glioma. Recently, antiviral therapies aimed at HCMV have demonstrated efficacy in patients with GBM. We have determined that Cidofovir (CDV), an FDA approved antiviral agent for CMV infection, potently inhibits GBM proliferation both in vitro and in an intracranial xenograft mouse model of primary GBM. Furthermore, our investigations of CDV have indicated that, while the antiviral effect is significant to the antitumr response, CDV possesses potent antitumor properties even in the absence of CMV infection. Importantly, the antitumor response seen using the in vivo GBM xenograft model with CDV is greater than any systemic agent tested thus far at UCSF other than temozolomide, and for temozolomide, substantial tumor response is limited to the use of tumor cell sources and their corresponding xenografts having methylated MGMT promoter. Mechanistically, we have determined that CDV, a cytosine analog, incorporates not only into CMV DNA but also into tumor cell genomic DNA. We find that CDV uptake by tumor cells activates apoptotic pathways and blocks normal DNA repair mechanisms, which are responsible for tumor cell resistance to and recovery following radiation therapy (RT), the primary standard of care treatment modality for newly-diagnosed GBM. In our in vitro and in vivo studies, CDV enhances the effect of RT. Although poor tissue uptake and nephrotoxicity are limitations of using CDV in treating human disease, our collaborator Dr. Karl Hostetler, has synthesized CDV derivatives that are highly lipophilic, and can be administered orally while causing minimum toxicity. In our preliminary studies, these compounds exhibit > 300-fold increased antitumor effect in vitro, thus allowing dramatically lower dosages to be administered, in comparison with cidofovir, for achieving significant anti-tumor activity. In Aim 1, we plan to use existing mouse xenograft models developed by our co-investigator Dr. David James at UCSF to optimize treatments based on acquired knowledge of investigational agent pharmacokinetics and to determine optimal regimens to use when combining inhibitors with RT. In Aim 2 we will utilize Dr. Chiocca's transgenic mouse model of spontaneously occurring glooms +/- CMV infection to understand the impact of antiviral therapy in the setting of CMV-mediated GBM tumor genesis. In addition, we will examine the impact of antiviral therapy with respect to the influence of CMV on the tumor microenvironment and host immune response to tumor. Finally, in Aim 3 we plan to investigate the mechanisms by which CDV and CDV-derived compounds elicit DNA damage and interfere with DNA repair mechanisms. We anticipate that one of the major advantages of these compounds will be their high therapeutic index: i.e., limited toxicity in normal cells, but dramati apoptotic pathway activation and prevention of DNA repair in tumor cells, which could significantly delay or possibly prevent radiation and chemo-resistance critical for GBM recurrence.

描述（由申请人提供）：胶质母细胞瘤 (GBM) 是一种致命的原发性脑肿瘤，大多数患者在诊断后仍能存活 12-15 个月，尽管接受了标准护理治疗。我们发现人类巨细胞病毒 (HCMV) 在 GBM 中存在很高比例，并且这些发现已得到多个小组的证实。我们的合作研究员 Nino Chiocca 博士最近证明，在转基因小鼠神经胶质瘤模型中，CMV 感染会加速肿瘤进展为 GBM。最近，针对 HCMV 的抗病毒疗法已证明对 GBM 患者有效。我们已经确定西多福韦 (CDV) 是 FDA 批准的用于 CMV 感染的抗病毒药物，在体外和原发性 GBM 的颅内异种移植小鼠模型中均能有效抑制 GBM 增殖。此外，我们对 CDV 的研究表明，虽然抗病毒作用对于抗肿瘤反应很重要，但即使在没有 CMV 感染的情况下，CDV 也具有有效的抗肿瘤特性。重要的是，使用带有 CDV 的体内 GBM 异种移植模型观察到的抗肿瘤反应比迄今为止在 UCSF 测试的除替莫唑胺外的任何全身药物都要强，并且对于替莫唑胺，实质性肿瘤反应仅限于使用肿瘤细胞来源及其相应的具有甲基化 MGMT 启动子的异种移植物。从机制上讲，我们已经确定 CDV（一种胞嘧啶类似物）不仅掺入 CMV DNA，而且掺入肿瘤细胞基因组 DNA。我们发现肿瘤细胞摄取 CDV 会激活细胞凋亡途径并阻断正常的 DNA 修复机制，这些机制负责肿瘤细胞对放射治疗 (RT) 的抵抗和恢复，放射治疗 (RT) 是新诊断 GBM 护理治疗方式的主要标准。在我们的体外和体内研究中，CDV 增强了 RT 的效果。尽管组织吸收差和肾毒性是使用 CDV 治疗人类疾病的局限性，但我们的合作者 Karl Hostetler 博士已经合成了高度亲脂性的 CDV 衍生物，并且可以口服给药，同时引起最小的毒性。在我们的初步研究中，这些化合物在体外表现出超过 300 倍的抗肿瘤作用，因此与西多福韦相比，可以显着降低给药剂量，从而实现显着的抗肿瘤活性。在目标 1 中，我们计划使用我们的联合研究员 David James 博士在 UCSF 开发的现有小鼠异种移植模型，根据所获得的研究药物药代动力学知识来优化治疗，并确定抑制剂与 RT 联合使用时的最佳方案。在目标 2 中，我们将利用 Chiocca 博士的自发性忧郁+/- CMV 感染的转基因小鼠模型来了解抗病毒治疗对 CMV 介导的 GBM 肿瘤发生的影响。此外，我们还将研究抗病毒治疗对CMV对肿瘤微环境和宿主对肿瘤的免疫反应的影响。最后，在目标 3 中，我们计划研究 CDV 和 CDV 衍生化合物引起 DNA 损伤并干扰 DNA 修复机制的机制。我们预计这些化合物的主要优点之一将是它们的高治疗指数：即对正常细胞的毒性有限，但能显着激活凋亡途径并防止肿瘤细胞中的 DNA 修复，这可以显着延迟或可能防止对 GBM 复发至关重要的放射和化疗耐药性。