Therapeutic efficacy of a novel FAK inhibitor TAE226 in ovarian carcinoma

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 3751 Objective: Focal adhesion kinase (FAK) overexpression is frequently found in ovarian and other cancers and is predictive of poor clinical outcome. In the current study, we characterized the biological and therapeutic effects of a novel FAK inhibitor,TAE226. Methods: Taxane-sensitive (SKOV3ip1 and HeyA8) and taxane-resistant (HeyA8-MDR) cell lines were used for in vitro and in vivo therapy experiments using TAE226 alone and in combination with docetaxel. Assessment of cell proliferation (PCNA), angiogenesis (CD31 staining) and apoptosis (TUNEL) was performed by immunohistochemical and immunofluorescence techniques. Results: In vitro , TAE226 inhibited phosphorylation of FAK at both Y397 and Y861, inhibited cell growth in a time- and dose- dependent manner, and enhanced docetaxel-mediated growth inhibition by 10 and 20 fold in the taxane-sensitive and resistant cell lines, respectively. In vivo , FAK inhibition by TAE226, significantly reduced tumor burden in the HeyA8, SKOV3ip1, and HeyA8-MDR models compared to the vehicle treated controls. Treatment with both TAE226 and docetaxel had greater efficacy than either agent alone in all three models (HeyA8: 75% reduction; p<0.002; SKOV3ip1: 97% reduction; p<0.001; HeyA8-MDR: 70% reduction; p<0.04). In addition, TAE226 alone and in combination with chemotherapy prolonged survival in tumor-bearing mice. Even in larger tumors, combination therapy with TAE226 and docetaxel resulted in tumor regression, as determined by bioluminescent imaging. Combination therapy induced apoptosis of tumor-associated endothelial cells and reduced microvessel density and tumor cell proliferation compared to control and single-agent therapy. Conclusions: TAE226 in combination with docetaxel is highly effective for the treatment of ovarian carcinoma. Therefore, FAK inactivation may be an attractive therapeutic approach against ovarian cancer.