Targeting the anti-apoptotic protein survivin in glioma

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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.