UCLA SPORE in Brain Cancer

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PROJECT SUMMARY/ABSTRACT – Overall The objectives of the UCLA SPORE in Brain Cancer are to contribute significantly to progress in the diagnosis, prognosis, and treatment of brain cancer. These goals will be accomplished through multiple and diverse research projects involving mechanistic pre-clinical work and innovative clinical studies, with a particular focus on developing novel strategies to overcome the problem of treatment-induced resistance. The broad, long-term objectives and aims of our brain cancer SPORE are as follows: 1) to investigate mechanisms of immunotherapy-induced immune evasion following active immunotherapy, and develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment; 2) to elucidate the alterations in cellular metabolism associated with drug- induced resistance to apoptosis, and exploit targeting apoptotic blocks to induce intrinsic tumor cell death; and 3) to explore the concept of radiation-induced phenotype conversion of non-tumorigenic cells to glioblastoma-initiating cells as a mechanism for radiation-induced resistance, and test new therapeutics to block such glioma stem cell conversion. In order to achieve these translational research goals of our program, we propose three main projects involving: 1) targeting immunotherapy-induced resistance with DC vaccination and PD-1/CSF-1R inhibition; 2) overcoming drug-induced resistance to intrinsic apoptosis in glioblastoma; and 3) strategies against radiation-induced cellular plasticity in glioblastoma. These translational research projects will be supported by four shared resource cores in administration, biospecimen/pathology, neuroimaging, and biostatistics/bioinformatics. Our program has also been successful in actively incorporating researchers in our Developmental Research and Career Enhancement Programs in order to foster new approaches for assessing and treating brain cancer. Our diverse array of novel SPORE projects and state-of-the-art cores has already made a significant impact on brain cancer research during the last funding cycle, and we hope to continue to make impactful contributions to the field well into the future. Each project has been developed jointly by teams of basic and clinical researchers, with the thoughtful advisement of our internal advisory board (IAB) and external advisory board (EAB), working together in a trans-disciplinary manner to address the most vexing problem in brain cancer – the development of treatment resistance. All three proposed projects are highly translational and will reach new human endpoints within the context of our next SPORE grant period.