TM-03. EFFECTS OF COMBINATION OF FICLATUZUMAB WITH ANTI-VEGF INHIBITORS ON GLIOBLASTOMA XENOGRAFTS

Glioblastoma development should be subdivided in three phases, one prehypoxic and two post-hypoxic phases. The pre-hypoxic phase, ranging from 10% to 5% oxygen (normal brain oxygen levels), should be characterized only by CD133- cells, and these cells are inevitably also those that first conquer and microinfiltrate the brain parenchyma. In some areas of the bulk, the oxygen concentration falls to about 5% or less, and hypoxia develops. The second phase ranges from about 5% to about 1% oxygen concentration. This phase of mild and severe hypoxia is regulated by the epigenetic shift driven by HIF2a, which is expressed only in cancer stem cells (CSCs) and is correlated with CD133 expression. When oxygen levels fall in certain regions of the tumor to about 1% or less, the third phase of very severe hypoxia begins. This phase is driven by HIF1a, which is expressed both by CSCs and committed cells. To date, the only way to monitor the development of the growing tumor in animal model is imaging. However, in order to reproduce what really happens in a human patient affected by a glioblastoma, we need a model that allows cells, biopsies, and sections to be obtained throughout tumor development. I recently proposed an original animal model that can enable us to studyand monitor the entire development of the glioblastoma in only one generation of mice. The model allows the creation of a pool of twin transplanted animals in the same condition and the study of glioblastoma development, both in the bulk and in the brain parenchyma. This is done by taking multiple biopsies and by performing multiple stainings on sections. Through parenchymal biopsies and stainings on sections, we have four means to identify the CSCs microinfiltrated in the brain with the possibility of targeting them.