Targeting the anti-apoptotic protein survivin in glioma

靶向神经胶质瘤中的抗凋亡蛋白生存素

• 批准号: 6815987
• 负责人: ROBERT A FENSTERMAKER
• 金额: $ 24.51万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-20 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6815987
• 关键词: apoptosis; autoimmunity; biotechnology; cell growth regulation; cell line; cellular immunity; chemical structure function; epitope mapping; gene mutation; glioma; immune tolerance /unresponsiveness; laboratory rat; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; species difference; survivin; tumor antigens; vaccine development; vaccine evaluation; vector vaccine

DESCRIPTION (provided by applicant): Malignant gliomas cause severe neurologic dysfunction and death. They are among the most aggressive and devastating of all human cancers. Conventional treatments have improved survival rates very little. Malignant gliomas may be susceptible to immunologically mediated attack. The long-range goal of our research program is to characterize the effects of DNA and cellular vaccines against molecular targets in malignant gliomas and to develop more effective strategies for inducing anti-tumor immunity. This proposal is based on our preliminary observation that a xenogeneic DNA vaccine against the anti-apoptotic protein "survivin" inhibits the growth of glioblastoma in rats via CD8-mediated attack. We will study DNA and cellular vaccines designed to evoke an immunologic attack on glioma cells expressing the tumor-specific survivin protein. The specific aims are to test the hypotheses that: 1) Xenogeneic differences between rat and human survivin sequences can be exploited to develop more immunogenic DNA and cellular glioma vaccines. 2) Molecular mimics of rat survivin epitopes can stimulate more effective anti-tumor responses against gliomas. 3) Tumor site plays a role in the ability of the anti-survivin immune response to recognize and control glioma growth. We will use immunogenic domains of the rat and human survivin genes to create both DNA and killed cellular vaccines. The cellular immune responses to these vaccines will be studied in naive rats without tumors. The rat and human survivin genes will be used to determine whether xenogeneic amino acid sequence differences (molecular mimicry) of the human protein will affect the nature and intensity of the immune response to vaccine. We will also use a syngeneic rat (F98) glioma model with endogenous survivin expression to test the ability of rat and human survivin DNA and cellular vaccines to inhibit tumor growth. The proposed experiments will address the possibility that molecular mimics of rat survivin protein domains may stimulate tumor-specific immune responses that break tolerance to the endogenous rat survivin protein and provide a clinically relevant model to study vaccination strategies against malignant gliomas. The purpose of the pre-clinical studies outlined here is to investigate the potential for the development of antisurvivin vaccines for eventual clinical investigation in the treatment of human gliomas.

描述（由申请人提供）：恶性胶质瘤导致严重的神经功能障碍和死亡。它们是所有人类癌症中最具侵略性和破坏性的。传统的治疗方法几乎没有提高存活率。恶性胶质瘤可能易受免疫介导的攻击。我们研究计划的长期目标是描述DNA和细胞疫苗对恶性胶质瘤分子靶点的作用，并开发更有效的诱导抗肿瘤免疫的策略。这个建议是基于我们的初步观察，即异种DNA疫苗的抗凋亡蛋白“生存素”抑制胶质母细胞瘤的生长在大鼠通过CD8介导的攻击。我们将研究DNA和细胞疫苗，旨在引起对表达肿瘤特异性生存素蛋白的神经胶质瘤细胞的免疫攻击。具体的目的是检验以下假设：1）大鼠和人生存素序列之间的异种差异可以被利用来开发更具免疫原性的DNA和细胞胶质瘤疫苗。2)大鼠生存素表位的分子模拟物可以刺激针对胶质瘤的更有效的抗肿瘤反应。3)肿瘤部位在抗生存素免疫应答识别和控制胶质瘤生长的能力中起作用。我们将使用大鼠和人类生存素基因的免疫原性结构域来创建DNA疫苗和灭活细胞疫苗。将在无肿瘤的未处理大鼠中研究对这些疫苗的细胞免疫应答。大鼠和人生存素基因将用于确定人蛋白质的异种氨基酸序列差异（分子模拟）是否会影响对疫苗的免疫应答的性质和强度。我们还将使用具有内源性生存素表达的同基因大鼠（F98）胶质瘤模型来测试大鼠和人生存素DNA和细胞疫苗抑制肿瘤生长的能力。拟议的实验将解决的可能性，大鼠生存素蛋白结构域的分子模拟物可能会刺激肿瘤特异性免疫反应，打破对内源性大鼠生存素蛋白的耐受性，并提供一个临床相关的模型，研究针对恶性胶质瘤的疫苗接种策略。本文概述的临床前研究的目的是研究开发抗生存素疫苗用于治疗人类胶质瘤的最终临床研究的潜力。