Abstract B253: The IGF1R inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-Stat3-HIF1 pathway in human glioblastoma cells

Abstract

Abstract Glioblastomas (GBMs) typically develop hypoxic areas within the tumor mass, which for some cells results in necrosis, but for others leads to pleiotropic adaptive changes promoting tumor progression through activation of survival pathways, disruption of apoptosis, increase in invasive potential and neovascularization. The transcription factor HIF1 (hypoxia-inducible factor 1) is known to play a major role in directing this adaptive program, following stabilization of its inducible -subunit under hypoxic conditions; however, HIF1 activity can also be enhanced by oxygen-independent mechanisms upon activation of growth factor receptors and their downstream signal transduction pathways. The present study investigates a) the possible presence of a regulatory loop linking IGF1R and HIF1 in human glioblastoma cells; b) the role played by the signal transducer and activator of transcription 3 (Stat3) in this pathway; and c) the ability of the IGF1R inhibitor NVP-AEW541 (Novartis Pharma, Basel, CH) to disrupt this pathway. We show that activation of IGF1R by its ligand IGF1 causes Stat3 activation, increased levels of HIF1α and increased release of VEGF, the product of one of the major target genes for HIF1 transcriptional activity. Treatment with NVP-AEW541 reverses all these changes, and so does transfection of the cells with a dominant negative form of Stat3. Interestingly, we also observe that IGF-independent activation of HIF1, obtained in the presence of the hypoxia mimic CoCl2, results in IGF1R activation, thereby indicating that a two-way relationship exists between growth factor receptor activation and increase in HIF1 transcriptional activity; NVP-AEW541 treatment significantly reduces both HIF1α protein levels and IGF1R tyrosine-specific phosphorylation in CoCl2-treated cells. Because cells surviving under hypoxic condition often become resistant to radiotherapy and chemotherapy, modulation of the IGF1R-HIF1 pathway could be a viable approach to increase the effectiveness of conventional cytotoxic agents; as GBM typically presents hypoxic areas, this strategy might prove particularly valuable in improving the poor prognosis of patients affected by this tumor type. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B253.