[Enzastaurin and Velcade versus multiple myeloma]
>>Blood. 2006 Oct 5; [Epub ahead of print
Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor Enzastaurin (LY317615.HCl).
Podar K, Raab MS, Zhang J, McMillin D, Breitkreutz I, Tai YT, Lin BK, Munshi N, Hideshima T, Chauhan D, Anderson KC.
Dana-Farber Cancer Institute.
In multiple myeloma (MM) protein kinase C (PKC) signaling pathways have been implicated in cell proliferation, survival, and migration. Here we investigated the novel, orally available PKC-inhibitor Enzastaurin for its anti-MM activity. Enzastaurin specifically inhibits phorbolester-induced activation of PKC isoforms, as well as phosphorylation of downstream signaling molecules MARCKS and PKCmicro. Importantly, it also inhibits PKC-activation triggered by growth factors and cytokines secreted by bone marrow stromal cells (BMSCs); co-stimulation with fibronectin, vascular endothelial growth factor (VEGF) or interleukin-6 (IL-6); as well as MM patient serum. Consequently, Enzastaurin inhibits proliferation, survival and migration of MM cell lines and MM cells isolated from multidrug-resistant patients; as well as overcomes MM cell growth triggered by binding to BMSCs and endothelial cells. Importantly, strong synergistic cytotoxicity is observed when Enzastaurin is combined with bortezomib, moderate synergistic or additive effects when combined with melphalan or lenalidomide. Finally, tumor growth, survival and angiogenesis are abrogated by Enzastaurin in an in vivo xenograft model of human MM. Our results therefore demonstrate in vitro and in vivo efficacy of the orally available PKC inhibitor Enzastaurin in MM and strongly support its clinical evaluation, alone or in combination therapies, to improve patient outcome in MM.<<
Enzastaurin is from Lilly; in PIII trials.
Cheers, Tuck |
