Effects of the Indazolylpyrimidine GW786034 on Angiogenesis and MM Cell Growth: Therapeutic Implications.

Vascular endothelial growth factor (VEGF) and its receptors play an important role in the pathogenesis of multiple myeloma (MM). Specifically, VEGF, which is present in the MM bone marrow (BM) microenvironment, induces neovascularization; triggers tumor cell growth, survival, and migration; inhibits dendritic cell maturation; and induces osteoclastogenesis. Therefore, the VEGF receptor provides a potential novel therapeutic target in MM. Previous studies showed that GW654652, a pan VEGFR inhibitor, inhibits growth and migration of MM tumor cells (Podar et al. Blood. 2004; 103:3473–3479.). Here we describe the effects of GW786034, a derivative of GW654652, on MM cells to support its potential clinical evaluation in MM patients. GW786034 inhibits VEGF- triggered Flt-1 phosphorylation and activation of downstream signaling molecules, induces concentration-dependent MM cell and HUVEC apoptosis, and inhibits VEGF- triggered MM cell migration. Specifically, GW786034 induces cleavage of caspase-8 and PARP, but not caspase-9, and induces downregulation of the pro-apoptotic molecules survivin, cIAP1, 2, and Mcl-1. Furthermore, GW786034 decreases proliferation of MM cells induced by their adhesion to BMSCs, and inhibits VEGF-induced upregulation of ICAM-1 and VCAM-1, thereby abrogating their adhesion to HUVECs. Consistent with these results, GW786034 inhibited both tubuli formation and accumulation of tumor cells at vascular branching points in a Matrigel tube forming assay. Finally, GW786034 sensitizes both MM cells alone and tumor cells bound to BMSCs or HUVECs to melphalan and bortezomib. Taken together, these studies support clinical evaluations of GW786034 either alone or in combination with other agents in MM patients.