Phase III trial of adjuvant 13-cis-retinoic acid and interferon-alpha for patients with aggressive skin squamous cell carcinoma.

5658 Vascular endothelial growth factor (VEGF) and its receptors play an important role in the pathogenesis of multiple myeloma (MM). VEGF present in the MM bone marrow microenvironment induces neovascularization, triggers tumor cell growth, survival and migration, inhibits dendritic cell maturation, and promotes osteoclastogenesis. VEGF therefore provides a potential novel therapeutic target in MM. Here we investigated a novel and potent VEGF receptor inhibitor, pazopanib. In vitro, pazopanib inhibits VEGF- triggered VEGF receptor phosphorylation and activation of downstream signaling molecules including Src kinase in MM cells and blocks MM cell migration, growth and survival. Moreover, gene expression and signaling network analysis in pazopanib- treated cells demonstrate transcriptional changes of several signaling pathways. Most prominently among these is a dramatic downregulation of cMyc. siRNA targeting cMyc blocked VEGF production and secretion in MM cell lines. In addition, pazopanib reduced VEGF in the microenvironment and directly inhibited endothelial cell growth, migration and vessel formation. Furthermore, pazopanib inhibited VEGF- induced upregulation of adhesion proteins on both endothelial and MM cells, thereby abrogating endothelial cell -MM cell adhesion and associated tumor cell proliferation. Pazopanib also strongly sensitized tumor cells bound to endothelial cells to DNA- damaging chemotherapeutic agents (i.e. melphalan), immunomodulatory drugs, and bortezomib. Similar activity of pazopanib was demonstrated using a MM xenograft mouse model. In summary, this is the first report showing anti- MM activity of an antiangiogenic compound in both in vitro and in vivo strongly supporting its clinical evaluation, alone or in combination with other therapies.