AMG 102, a fully human anti-hepatocyte growth factor/scatter factor neutralizing antibody, enhances the efficacy of temozolomide or docetaxel in U-87 MG cells and xenografts

Purpose: Hepatocyte growth factor (HGF/SF) and its receptor c-Met have previously been shown to be up-regulated in multiple human cancers, including glioblastoma multiforme. To better understand if AMG 102, a fully human, anti-HGF/SF-neutralizing antibody, could be incorporated into current clinical practice, AMG 102 was tested preclinically in combination with temozolomide or docetaxel to determine if enhanced efficacy was observed compared with AMG 102 alone. Experimental Design: The effects of AMG 102 were tested for antiproliferative activity in combination with temozolomide or docetaxel on U-87 MG cells in vitro and for antitumor activity in a U-87 MG xenograft model in vivo. Apoptotic activity was also measured for AMG 102 and docetaxel combined in vitro. Results: Treatment with temozolomide combined with AMG 102 resulted in increased inhibition of cell growth in vitro compared with treatment with either single agent alone. In U-87 IVIG xenografts in vivo, AMG 102 combined with temozolomide or docetaxel significantly increased the inhibitory effect on tumor growth when compared with treatment with either agent alone (P < 0.0001 and P ( 0.015, respectively). In vitro, docetaxel alone induced both caspase-3/7 activity as well as poly(ADP)ribose polymerase and caspase-7 cleavage in U-87 IVIG cells; these events were enhanced when used in combination with AMG 102. Importantly, there was no evidence of interference between AMG 102 and either temozolomide or docetaxel in vitro or in vivo. Conclusion: These studies support testing of AMG 102 in combination with temozolomide or docetaxel. Such combinations may represent promising, novel clinical therapeutic strategies for cancers that are dependent on the HGF/SF/SF:c-Met pathway in the oncology setting.