The prognosis for children and adults with malignant brain tumors has improved minimally during the last two decades; median survival remains less than one year for patients with malignant glioma, the most common intrinsic brain tumor. These statistics provide a strong rationale for coordinate efforts to identify innovative approaches for the treatment of these tumors. The unifying hypothesis of this program project grant is that novel therapeutic strategies that take into account the unique features of central nervous system tumors will induce tumor regression, and will potential the efficacy of conventional therapies. Each project is translationally oriented, with a common goal of addressing fundamental biological issues relevant to the tumor growth process and evaluating innovative treatment approaches using a series of preclinical glioma models, as a basis for identifying promising strategies that can be advanced into clinical therapeutics. Project 1 is based on the hypothesis that inhibition of the aberrantly activated signal transduction pathways of malignant gliomas, or direct activation of apoptosis signaling pathways, will induce glioma cell killing, potentially in a genotype-specific fashion, and that this approach will have independent therapeutic activity in preclinical glioma models, and potentiate the effects of other approaches. Project 2 postulates that apoptotic or necrotic glioma cells, such as those produced by promising agents from Project 1, will constitute an optimal mechanism for antigen delivery to antigen presenting cells, and that the conditions for active immunization with such cells can be optimized to promote an effective anti-0tumor immune response. Project 3 postulates that gene delivery, using replication-defective Herpes virus vectors incorporating novel multi-gene constructs engineered to facilitate transcellular transfer of therapeutically relevant gene products, can achieve tumor cell killing and enhance the effects of other treatment strategies. This project will also generate many of the vector constructs that will be used in Projects 1 and 2. The Administrative/Biostatistics/Clinical Support Core (A) provides essential infrastructure support for the basic and clinical research activities of the component projects and other cores. The Cellular and Tissue Imaging Core (B) provides a panopoly of advanced microscopic imaging capabilities used in each of the component projects. The Immunological Monitoring and Cellular Products Laboratory Core (C) provides banking of tissue and serum samples for each of the projects, maintenance of native and transduced cell lines, preparation of biological products, and comprehensive therapeutic monitoring that are essential for the innovative pilot clinical protocols incorporated within this program. Taken together, the multi-disciplinary interactions that have evolved within the context of this program of this program optimize our changes to identify and refine promising therapeutic approaches that can be applied clinically to improve the otherwise discouraging prognosis of patients with malignant gliomas.
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