The most common cancer originating in the adult brain, glioblastoma (GBM), is uniformly fatal with a life expectancy of less than 2 years. This dismal prognosis is attributed to its invasive growth, molecular and cellular heterogeneity, treatment resistant cancer stem cells and suppression of the immune system. Cure or significant improvement in GBM is limited by the lack of animal models that reproduce these hallmark features. The most common rodent models are vastly different from human and surgical interventions are difficult to simulate. By contrast, the mini-pig brain is remarkably similar to human and its larger size permits relevant surgical and imaging studies. Therefore we propose ...

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The most common cancer originating in the adult brain, glioblastoma (GBM), is uniformly fatal with a life expectancy of less than 2 years. This dismal prognosis is attributed to its invasive growth, molecular and cellular heterogeneity, treatment resistant cancer stem cells and suppression of the immune system. Cure or significant improvement in GBM is limited by the lack of animal models that reproduce these hallmark features. The most common rodent models are vastly different from human and surgical interventions are difficult to simulate. By contrast, the mini-pig brain is remarkably similar to human and its larger size permits relevant surgical and imaging studies. Therefore we propose to develop a first in kind syngeneic (intact immune system) glioma model in the mini-pig to recapitulate defining features of human glioma which will support studies heretofore impossible in rodent models or human patients. We will generate malignant glioma cells from presumed glioma cells of origin and implant them into host pigs with intact immune systems. The relevance of the model will be established through analysis of accepted hallmark MR imaging and pathology features of the human disease. We expect to recapitulate the MRI and pathologic features of human GBM including invasive growth. The validation of the model is a critical first step towards addressing key unanswered questions which currently limit the potential for cure of this deadly disease. For instance, i) how surgical resection alters the tumor environment and drives growth of heterogeneous and uniquely resistant cancer cells, ii) how residual invasive cells after surgery contribute to treatment resistance and progression, and iii) how the immune environment is altered or contributes to progression? In addition, the development of this reproducible model addresses a critical need for platforms to reliably test new therapies, surgical techniques and drug delivery systems as a bridge to clinical application.

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