Integrative Approaches to Stroma-Directed Glioma Therapy

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DESCRIPTION (provided by applicant): In summary, this proposal focuses on two of the five themes outlined in the RFA-OD-10-005: "Applying Genomics and Other High Throughput Technologies" and "Translating Basic Science Discoveries into New and Better Treatments" and is ready for immediate implementation. Brain tumors are complex microcosms in which bi-directional interactions between neoplastic cells and non-neoplastic cells drive tumorigenesis and tumor progression. Our limited knowledge of the complex interplay between tumor cells and the tumor surround is a considerable obstacle to fully appreciating brain tumor biology, and most likely represents a significant barrier to successful brain tumor treatment outcomes. Studies from our laboratories using genetically-engineered mice have demonstrated the obligate role of the tumor microenvironment (stroma) in dictating when and where gliomas form and grow. In particular, we have shown that resident non-neoplastic immune system-like cells (microglia) in these tumors elaborate specific growth-promoting factors critical for glioma formation and maintenance. In this proposal, we have assembled a team of investigators with expertise in cross-disciplinary science and prior involvement in large-scale cooperative research initiatives, and focused their efforts on identifying targetable molecules made by microglia present in the tumor microenvironment for preclinical evaluation. Specifically, we plan to extend our ongoing studies with The Genome Center at Washington University School of Medicine to use next-generation sequencing and bioinformatics pipelines to discover new markers and signals shared by mouse and human glioma-associated microglia, and which represent potential targets for stromal-directed therapy (Phase 1). Identified genes will be used to develop immunologic reagents for the subclassification of tumor-associated microglia (Phase 2a) as well as to discover novel glioma-promoting factors ("gliomagens") (Phase 2b). Monoclonal antibodies developed in Phase 2a will next be employed to classify microglia subsets into functionally distinct populations and to determine the relevance of specific microglia populations to clinical tumor behavior (Phase 3a). In addition, lead microglia gliomagens validated by lentiviral manipulation in Nf1 genetically-engineered mouse (GEM) strains (Phase 2b) will be evaluated by high-throughput technology using a stromal co-culture system to identify stromal-directed pharmacologic inhibitors for future preclinical therapeutic studies (Phase 3b). PUBLIC HEALTH RELEVANCE: Brain tumors (gliomas) are the leading cause of cancer-related death in children with few successful treatments available. This proposal applies genomics and novel high throughput technologies to translate basic science discoveries into new and better treatments for children with low-grade glioma.