Tumor angiogenesis is a degenerate process regulated by a complex network of proangiogenic factors. Existing antiangiogenic drugs used in clinic are characterized by selectivity for specific factors. Antiangiogenic properties might be improved in drugs that target multiple factors and thereby address the inherent mechanistic degeneracy in angiogenesis. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family members and their cognate receptors are key players in promoting tumor angiogenesis. Here we report the pharmacologic profile of E-3810, a novel dual inhibitor of the VEGF and FGF receptors. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2, and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range. Ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 was suppressed along with human vascular endothelial cell growth at nanomolar concentrations. In contrast, E-3810 lacked cytotoxic effects on cancer cell lines under millimolar concentrations. In a variety of tumor xenograft models, including early-or late-stage subcutaneous and orthotopic models, E-3810 exhibited striking antitumor properties at welltolerated oral doses administered daily. We found that E-3810 remained active in tumors rendered nonresponsive to the general kinase inhibitor sunitinib resulting from a previous cycle of sunitinib treatment. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic FGF-induced angiogenesis and reduced blood vessel density as assessed by histologic analysis. Dynamic contrast-enhanced magnetic resonance imaging analysis confirmed that E-3810 reduced the distribution of angiogenesis-sensitive contrast agents after only 5 days of treatment. Taken together, our findings identify E-3810 as a potent antiangiogenic small molecule with a favorable pharmacokinetic profile and broad spectrum antitumor activity, providing a strong rationale for its clinical evaluation. Cancer Res; 71(4); 1396-405. Ó2011 AACR.
It has been widely recognized that histone deacetylases (HDAC) are promising targets in the field of oncology. An impressive body of preclinical research points to the ability of HDAC inhibitors (HDACIs) to modulate a wide variety of cellular functions, including cell differentiation, cell cycle progression, apoptosis, cytoskeletal modifications and angiogenesis. Originally developed as epigenetic drugs because of their ability to inhibit histones deacetylation, HDACIs are now being considered also because of their effects on other acetylation-regulated proteins with pivotal roles in transformed cells. This review will highlight the clinical development of HDACIs in oncology and will try to discuss the several major open clinical issues challenging the successful clinical development of HDACIs, with a particular emphasis on the spectrum of activity of these agents, the best development strategy in solid tumors, the cardiac side effects and bio-markers to be used in clinical trials.
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