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Despite recent advances in general cancer treatment, glioblastoma remains among the most lethal of human malignancies. Even with aggressive multimodal radiation and chemotherapy after surgery, glioblastoma recurs with a bleak prognosis. Decades of research focused on strategies such as increasing radiation sensitivity and interference with oncogenic signal transduction have yielded only incremental improvements at best. This is due in part to the radioresistance of glioblastoma and molecular heterogeneity of tumor cells. We hypothesize is that the development of more effective glioblastoma therapies will require: (i) a more accurate molecular analysis of glioblastoma so as to predict response to therapy; (ii) better genetically engineered mouse models, which can faithfully recapitulate human glioblastoma and the tumor microenvironment to test new approaches and (iii) development and application of more accurate and focused methods to deliver sustained high energy particles to glioblastoma tumor sites. This chapter describes the current state-of-the-art molecular analysis approaches, latest in glioma mouse modelling, and advances in the application of proton therapy treatment and research. By integrating basic and clinical research with cutting-edge technologies, a mechanistic understanding of glioblastoma therapy resistance and pathogenesis and the development of new therapeutics to overcome the therapeutic resistance of glioblastoma will be advanced.
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