THERAPY OF INTRACRANIAL MELANOMA WITH HERPES VIRUS

疱疹病毒治疗颅内黑色素瘤

• 批准号: 2108985
• 负责人: BRUCE P RANDAZZO
• 金额: $ 0.05万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1995-12-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2108985
• 关键词: antiviral antibody; cytokine; cytolysis; disease /disorder model; ganciclovir; genetic transcription; genotype; herpes simplex virus 1; immunocytochemistry; in situ hybridization; laboratory mouse; latent virus infection; melanoma; mutant; neoplasm /cancer therapy; nonhuman therapy evaluation; northern blottings; phenotype; thymidine kinase; transfection; virulence; virus RNA; virus antigen; virus genetics; virus replication

I have been totally committed to a career as an academic biomedical researcher for the past ten years. At every opportunity, I have attempted to achieve the finest research and clinical training possible. Now, realizing the important contributions that molecular virology can make to the area of cancer research, I wish to take advantage of a Clinical Investigator Award to gain experience in this emerging field. I joined the faculty of the Department of Dermatology at The University of Pennsylvania two years ago. The Department is very much committed to my academic development, and I have spent most of my time in the laboratory of Dr. Nigel Fraser of The Wistar Institute. His lab has been consistently productive in the areas of Herpes Simplex virus type I (HSV-1) latency and pathogenesis, and has recently made inroads into the use of HSV-1 as gene therapy vectors. The overall goal of this proposal is to examine the therapeutic usefulness of neuroattenuated HSV-1 mutants for the therapy of brain tumors. This will be achieved in an intracranial murine melanoma model. These HSV-1 mutants replicate preferentially in tumor cells, and not within the generally post-mitotic cells of the nervous system. We will determine if this selective replication can be utilized to lyse tumor cells within the CNS, without harming the host. The experiments outlined in this proposal will allow us to correlate the genotype of each HSV-1 mutant with a therapeutic phenotype. Ultimately, these data will allow for the design of HSV- 1 mutants optimized for tumor therapy. Using a variety of complementary molecular techniques, we will perform detailed studies of the pathogenicity, specificity, and fate of candidate viruses subsequent to treatment of mice bearing intracranial melanoma. We will examine the role of host primary and secondary anti-viral immunity. We will also investigate two strategies for augmenting the effectiveness of this therapeutic approach. First we will combine viral therapy and ganciclovir, and second we will construct HSV-1 mutants that express cytokine genes within tumor cells using a technique of in vitro ligation- transfection. Our preliminary data show that this is a viable approach to brain tumor therapy, that offers hope for new therapeutic directions at a time when available therapies are completely inadequate. The expertise of the primary and secondary sponsors in virology and tumor biology respectively, and the collective resources of The Wistar Institute and the University of Pennsylvania, make this a perfect environment in which to perform these studies. I am confident that by the end of this training period, I will have the skills and experience necessary to be a first rate independent investigator, and will have advanced the field of experimental cancer therapy.

我完全致力于学术生物医学的职业生涯 过去十年的研究员。在每一个机会，我都有 试图实现最好的研究和临床培训 可能的。现在，认识到分子的重要贡献 病毒学可以进入癌症研究领域，我希望采取 利用临床研究者奖获得以下方面的经验 这个新兴领域。 我加入了皮肤科的教员 两年前，宾夕法尼亚大学。该部门非常 我非常致力于我的学术发展，并且我花了大部分时间 我在 Wistar 的 Nigel Fraser 博士实验室的时光 研究所。他的实验室在以下领域一直保持高效 I 型单纯疱疹病毒 (HSV-1) 潜伏期和发病机制，以及 最近在使用 HSV-1 作为基因治疗方面取得了进展 向量。 该提案的总体目标是检查治疗方法 神经减毒 HSV-1 突变体用于治疗 脑肿瘤。这将在颅内小鼠中实现 黑色素瘤模型。这些 HSV-1 突变体优先在 肿瘤细胞，并且不在一般的有丝分裂后细胞内 神经系统。我们将确定这种选择性复制是否可以 用于裂解中枢神经系统内的肿瘤细胞，而不损害 主持人。本提案中概述的实验将使我们能够 将每个 HSV-1 突变体的基因型与治疗方法相关联 表型。最终，这些数据将允许 HSV 的设计 1 个针对肿瘤治疗进行优化的突变体。 使用各种互补的分子技术，我们将 对致病性、特异性和 携带小鼠治疗后候选病毒的命运 颅内黑色素瘤。我们将研究主机主要和 次级抗病毒免疫。我们还将调查两个 增强这种治疗效果的策略 方法。首先，我们将病毒疗法和更昔洛韦结合起来，并且 其次，我们将构建表达细胞因子基因的 HSV-1 突变体 使用体外连接技术在肿瘤细胞内- 转染。 我们的初步数据表明这是一种可行的大脑方法 肿瘤治疗，为新的治疗方向带来了希望 现有疗法完全不足的时期。 主要和次要申办者在病毒学方面的专业知识和 肿瘤生物学分别，以及集体资源 威斯塔研究所和宾夕法尼亚大学，使之成为 进行这些研究的完美环境。我是 相信在本次培训结束时，我将拥有 成为一流独立人士所需的技能和经验 研究员，并将推进实验领域 癌症治疗。