Enzastaurin (LY317615.HCl) enhances the efficacy of multiple anti-angiogenic agents, targeted therapies and standard oncolytics.
Authors: Ann McNulty, Stephen Parsons, Bruce Konicek, Spring Weir, Andrew Capen, Philip Schwier, Michele Dowless, Jennifer Stephens, Crystal Banks, Lysiane Huber, Yuefeng Chen, Jianyong Shou, Robin Goode, Louis Stancato, Libin Ma, Greg Tucker-Kellogg, Donald Thornton, James Starling, Jeremy Graff
Journal: Cancer Research (2008)

LB-104  Enzastaurin (LY317615.HCl) is currently in III clinical trials as well as multiple phase II trials as a single agent and in combination with a variety of standard chemotherapies, newer targeted agents and anti-angiogenics. Enzastaurin suppresses tumor-induced angiogenesis and induces tumor cell death in multiple human tumor cell lines by inhibiting PKC and PI3K/AKT pathway signaling. Because activation of these signaling pathways has been repeatedly linked to the development of chemo- and radio-resistance in multiple tumor types, and because anti-angiogenic therapies have been shown to enhance other targeted and oncolytic therapies, we sought to explore whether enzastaurin may enhance the efficacy of standard oncolytic or targeted anti-cancer therapies. Herein, we show that enzastaurin exhibits substantial anti-angiogenic activity at clinically achievable doses, preventing the formation of endothelial vessel-like structures when plated on a bed of dermal fibroblasts and reducing endothelial cell content in matrigel plugs after implantation into mice. Enzastaurin treatment also substantially represses the formation of the typical, highly branched, disorganized vasculature in A549 non-small cell lung cancers after intradermal implantation in nude mice. In combination with sunitinib (PO 20 or 40 mg/kg QD), enzastaurin (PO TID @ 100mg/kg) exhibited a more significant anti-tumor effect than either agent alone in both 786-0 and CaKi-1 renal cell carcinoma xenografts. In HT-29 colon cancer xenografts, enzastaurin + capecitabine (135 or 270 mg/kg QD IP) or enzastaurin + irinotecan (weekly x 3, 100mg/kg IP) significantly repressed tumor growth whereas single agent treatments failed to significantly reduce tumor growth. In prostate cancer, enzastaurin + taxotere (10mg/kg IP) repressed growth of hormone-independent PC-3 xenograft tumors more substantially than did taxotere alone. In LNCaP xenografts, enzastaurin + castration significantly repressed growth vs. castration alone. In cultured LNCaP cells and androgen-independent variants, enzastaurin treatment significantly repressed androgen receptor expression and reduced PSA expression. Finally, in U87MG and CRL2611glioblastoma xenografts, tumor growth was suppressed by both enzastaurin (100mg/kg TID PO) and temozolomide (TMZ, 3mg/kg 1X) as single agents to a limited extent but was almost completely repressed by the combination of enzastaurin with TMZ. Enzastaurin dramatically enhanced the induction of apoptosis and reduction of cellular proliferation by TMZ treatment in both 06MGMT + and - GBM cells lines, coincident with a blockade of signaling through the AKT pathway and p90RSK. Collectively, these data indicate that by blocking signaling through the PKC and PI3K/ AKT pathways in tumor and endothelial cells, enzastaurin enhances the efficacy of a wide range of chemo- and targeted therapies.