Abstract 3610: Potent preclinical anti-tumor activity of MGCD265, an oral Met/VEGFR multitargeted kinase inhibitor in clinical development, in combination with taxanes

Abstract

Abstract MGCD265, a multitargeted receptor tyrosine kinase inhibitor in clinical development, inhibits the activation of Met, VEGFR1, 2, 3, Tie-2 and Ron. Met is a promising molecular target for the development of cancer therapeutics and is found overexpressed and phosphorylated in a large proportion of NSCLC patients. Several agents targeting Met are currently under clinical investigation in NSCLC including MGCD265, and early clinical results are encouraging. Interestingly, to our knowledge, no Met inhibitor has been explored in NSCLC in combination with a taxane. In support of the clinical development of MGCD265, we have investigated preclinically the anti-tumor activity of MGCD265 in combination with taxanes. The combination of MGCD265 with docetaxel or paclitaxel resulted in enhanced anti-tumor activities compared to treatment with either agent alone in multiple xenograft models, including human NSCLC, glioblastoma, breast, prostate and gastric carcinomas. Enhanced efficacy occurred in the absence of overt toxicity. Moreover, PK analyses demonstrated lack of drug-drug interactions. Interestingly, in a gastric Met-driven carcinoma model in which MET is amplified (MKN45), treatment with MGCD265 in combination with docetaxel resulted in tumor regression at suboptimal doses of the taxane. Immunohistochemistry analyses in this model showed that this combination altered tumor vascularization as detected by endothelial cells labeling (CD31). While it has been suggested that changes in tumor vascularization may increase tumor exposure to docetaxel, the exposure of either MGCD265 or docetaxel was not altered in tumors treated with the combination. To gain insights into the molecular mechanism through which improved anti-tumor activities were achieved by the combination, we performed gene expression analyses on xenograft tumors. Genes differentially regulated by either agent alone were simultaneously regulated and sometimes enhanced, when the two agents were combined. Confirmations are currently ongoing. Together, these studies provide support for the development of MGCD265 in combination with taxanes for the treatment of cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3610. doi:10.1158/1538-7445.AM2011-3610