Blockade of tumoral processes by inhibition of angiogenesis and RAS protein activity

Résumé

Angiogenesis, the process of new blood vessel formation, is an essential requirement for the survival and proliferation of solid tumors. Accordingly, the search for angiogenesis inhibitors has become a leading line of investigation in anticancer research, and it has translated into several drugs in the market that have clearly improved outcomes in patients with different tumor types and metastatic disease. However, several limitations still exist, such as the lack of efficacy in some patients, the appearance of adverse effects, and drug resistance. It has been suggested that when the vascular endothelial growth factor (VEGF) signaling is pharmacologically blocked, other proangiogenic factors -especially the fibroblast growth factor (FGF)- take over its signaling, thereby supporting tumor angiogenesis. Besides, it has been described that increasing tumor hypoxia during antiangiogenic therapy enhances cell survival through the stimulation of several factors, particularly the hypoxia-inducible factor-1α (HIF- 1α).7 In this context, the main objective of the present work is the identification of new small molecules able to block angiogenesis affecting various proangiogenic factors (especially VEGF and FGF signaling pathways), and to induce a sustained inhibition of the proangiogenic signaling generated by hypoxia. This overall objective involves the following steps: 1. Hit identification and hit to lead process. 2. Biological characterization of selected compound(s) in terms of impairment of proangiogenic signaling under hypoxia. 3. Antitumor effect of selected compound(s)...