Anti-vascular endothelial growth factor (VEGF) therapies, such as bevacizumab, inhibit VEGF angiogenic actions and are increasingly used in the clinic as anticancer regimens for a variety of tumours, among which glioblastoma multiforme (GBM), the most lethal and angiogenic brain tumour, characterized by a high degree of heterogeneity. However, resistance to anti-angiogenic therapy, which leads to ineffectiveness of the existing drugs, is often acquired and suggests that there is urgent need to identify novel targets and develop alternative or complementary therapeutic options. Previous in vitro studies of the host lab have identified a novel receptor that binds VEGF and through co-operation with alpha v beta 3 integrin, is required for VEGF-induced endothelial and GBM cell migration. This receptor also mediates VEGF effects that are not inhibited by bevacizumab, encouraging the hypothesis that its targeting might be beneficial for at least some cases of resistance development to bevacizumab. The objectives of the current application are: 1) to study how VEGF interacts with this novel receptor in several different GBM cell lines, as well as in commercially available tissue arrays containing different grades of astrocytomas, and evaluate the physiological significance of such interaction, 2) To determine the interplay between this and other VEGF receptors/co-receptors, such as VEGFR-2, alpha v beta 3 integrin and nucleolin, and elucidate the cross-talk of their signalling pathways that subsequently activate the transcription factors NFAT and AP-1 and play a role in VEGF-induced cell migration, angiogenesis and inhibition of apoptosis. The project incorporates state of the art in vitro and in vivo approaches and is based on a multitude of disciplines, in order to validate an alternative target for GBM therapy, uncover novel or poorly explored signalling pathways, and identify potential bioactive molecules to be tested as inhibitors of GBM progression and angiogenesis.
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