TRANSLATIONAL DISCOVERY OF THERAPEUTIC TARGETS FOR GLIOBLASTOMA

Glioblastoma is a deadly brain tumor with a median survival of 1.3 years after surgery, radiotherapy and chemotherapy. The dismal prognosis is due to the propensity of the tumor to invade adjacent normal brain. Although next generation sequencing (NGS) led to genomic landscaping of glioblastoma, there is little insight into the mechanism of neoplastic cell invasion, the detection of the invasive cells or their therapeutic targeting. To address these critical issues, we developed a murine model of invasive glioblastoma that mimics the human disease. Using a cancer stem-cell like human glioblastoma cell line in an orthotopic model, we isolated pairs of neoplastic cells growing either in the core of the tumor, or away for the core, in invasive secondary foci. A phenotypic assessment showed significantly decreased animal survival, increased cancer stemness and invasion in the invasive cells in comparison to core cells. Expression profiling of Core and Inv cells resulted in the identification of differentially expressed gene targets controlling metabolic pathways, cell-cell and cell-matrix adhesion and cell differentiation. A 300 gene library, including these targets, was designed for NGS of high grade diffuse glioma cases. In a series of 4 pediatric and adult WHO grade IV diffuse glioma autopsy cases with a total of 28 sequenced distinct primary and secondary tumor foci, as well as normal brain, we found mutations in several of the genes identified in the mouse model. Two categories of novel targets potentially relevant for therapy were confirmed and further addressed: extracellular matrix proteases and metabolic enzymes. These translational findings and the implications for the molecular diagnosis and therapy of glioblastoma will be discussed.