Abstract

Glioblastomas are one of the most lethal cancers with very poor prognosis of survival .One of the remarkable feature of gliomas is that recurrence is nearly universal, and as few as 10-100 cells tumor cells can give rise to lethal tumors. Using lentiviral vectors to generate mouse models of glioblastoma multiforme (GBM) which faithfully phenocopies the human tumors anatomically, histological and by molecular signatures, we have shown that all tumors can originate in the brain from glial or neuronal cells . We show that terminally differentiated glial or neuronal cells can undergo dedifferentiation/reprograming upon transduction with oncogenes or removal of suppressor genes ,leading to formation of malignant gliomas.In the hypoxic regions of the tumors, the cells can transdifferentiate into endothelial cells ( TDE Cs) capable of making functional blood vessels, thus establishing the plasticity of the transformed cell . Consequently , drugs that block formation of normal blood vessels are unable to stop tumor growth because TDE Cs are devoid of VEGFR . We are using a variety of drugs to inhibit formation of TDE Cs. We are also pursuing the use of inhibitors of NFkB to block the tumor growth, and thus reduce the tumor burden and extend life span