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Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with an average incidence of 2-3 new cases per 100.000 in a population each year. GBM is a very heterogeneous tumor, though some molecular changes are characteristic for the disease. Among the most common are amplification or over expression of the Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase involved in proliferation, migration and tumor growth; mutation or deletion of PTEN, a crucial regulator of the PI3-k/Akt pathway important for survival and resistance to apoptosis; as well as over expression of several growth factors such as EGF, TGFα and VEGF. In addition, some GBMs express the tumor specific variant EGFRvIII which lacks part of the extracellular, ligand binding domain of the wild-type EGFR and which shows constitutive activation. The mutated receptor has been implicated in in vitro experiments and in animal models to confer an extra growth promoting and tumorigenic effect to the cells. On a macroscopic level, histopathologicalextensive areas of necrosis surrounded by pseudopalisading cells and excessive angiogenesis characterize GBMs. Despite multimodal therapy it is still not possible to cure patients with GBM, and the median survival after diagnosis is around 14 months. Due to its heterogenic nature it has long been postulated that individualized treatment is the best way to cure GBM patients and thus it is of great importance to study molecular mechanisms behind the disease, and to develop screening methods by which it will be possible to select patients for specific treatments.

Up to date there are no satisfactory in vitro models representing GBM, since EGFR amplification and over expression as well as expression of the tumor specific EGFR mutant EGFRvIII exclusively seem to be in vivo phenomenon. In order to establish a good model for GBM both in vivo and in vitro we have subcutaneously xenografted GBM tissue from patients diagnosed with GBM according to WHO 2000 guidelines onto the flanks of nude mice. The tumors have been serially passaged onto new mice when reaching the maximal ethical size. After each passage, the tumors have been diagnosed as GBM and the expression of EGFR, EGFRvIII and p53 has been investigated by IHC and Western blotting. When established on mice the tumors have been dissected out and allowed to grow in vitro. This model enables us to test new treatment modalities both in vitro and in vivo as well as to investigate the underlying mechanisms behind the disease. Data regarding the frequency of EGFR over expression and EGFRvIII expression as well as establishment of GBM cell lines will be presented at the meeting.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA