Targeting the anti-apoptotic protein survivin in glioma

描述(申请人提供)：恶性胶质瘤会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袭性和破坏性的癌症之一。常规治疗对存活率的提高微乎其微。恶性胶质瘤可能容易受到免疫介导的攻击。我们研究计划的长期目标是表征DNA和细胞疫苗对恶性胶质瘤分子靶点的影响，并开发更有效的策略来诱导抗肿瘤免疫。这一建议是基于我们的初步观察，即针对抗凋亡蛋白“Survivin”的异种DNA疫苗通过CD8介导的攻击抑制了大鼠胶质母细胞瘤的生长。我们将研究DNA和细胞疫苗，旨在激发对表达肿瘤特异性Survivin蛋白的胶质瘤细胞的免疫攻击。具体目的是验证以下假设：1)可以利用大鼠和人Survivin序列之间的异种差异来开发更具免疫原性的DNA和细胞胶质瘤疫苗。2)大鼠Survivin表位的分子模拟能激发更有效的抗胶质瘤免疫应答。3)肿瘤部位在抗Survivin免疫反应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Survivin基因的免疫原域来制造DNA疫苗和灭活细胞疫苗。对这些疫苗的细胞免疫反应将在没有肿瘤的幼鼠身上进行研究。大鼠和人类的Survivin基因将被用来确定人类蛋白质的异种氨基酸序列差异(分子模仿)是否会影响疫苗免疫反应的性质和强度。我们还将使用内源性Survivin表达的同基因大鼠(F98)胶质瘤模型来测试大鼠和人类Survivin DNA和细胞疫苗抑制肿瘤生长的能力。这些实验将探讨分子模拟大鼠Survivin蛋白结构域可能刺激肿瘤特异性免疫反应，从而打破对内源性大鼠Survivin蛋白的耐受性，并为研究恶性胶质瘤的疫苗接种策略提供一个临床相关的模型。这里概述的临床前研究的目的是为了研究抗Survivin疫苗的开发潜力，以最终用于治疗人脑胶质瘤的临床研究。

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.