Abstract C271: FAK inhibitor defactinib (VS-6063) enhances the efficacy of paclitaxel and preferentially targets ovarian cancer stem cells.

Abstract

Abstract Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that orchestrates cell signaling through integrins and growth factor receptors and plays important roles in tumorigenesis. Amplification and overexpression of FAK have been observed in aggressive human cancers including ovarian and breast cancers. Defactinib is a potent, selective, and orally active FAK inhibitor with demonstrated tolerability and preliminary clinical activity as a single agent in a Phase 1 clinical trial. In an ongoing Phase 1/1b clinical trial (NCT01778803), we have demonstrated that defactinib can be combined with paclitaxel and have observed preliminary signs of clinical activity. We report here preclinical data supporting the clinical testing of defactinib in combination with paclitaxel in patients with ovarian cancer. In human ovarian cancer cell lines TOV-21G and OV-7, defactinib was found to enhance the efficacy of paclitaxel. Combination Index analyses demonstrated synergistic inhibition of tumor cell proliferation/survival with combination of defactinib and paclitaxel. We find that FAK inhibitors preferentially target breast and ovarian cancer stem cells (CSCs) relative to bulk tumor cells as evidenced by a diminished proportion of CSCs in multiple orthogonal CSC assays. In direct contrast, the standard-of-care cytotoxic agents, paclitaxel and carboplatin, increased the percentage of CSCs, indicating that these agents do not effectively target CSCs. Importantly, combination of FAK inhibitors with cytotoxic agents attenuated the enrichment of CSCs induced by the cytotoxic agents. We subsequently determined if defactinib reduces CSCs in tumor specimens from ovarian cancer patients who were previously treated with taxane and platinum. Ex vivo treatment of ovarian tumor tissue fragments with defactinib reduced the percentage of CSCs as assessed by CD24hi/CD117hi CSC markers and the Aldefluor assay. To assess drug effects on tumor-initiating capability, the ‘gold standard’ for CSC activity, TOV-21G cells were pretreated in vitro with the FAK inhibitor, paclitaxel or the combination of both agents and 1,000 of the resulting cells were injected into immunodeficient mice. The FAK inhibitor alone or in combination with paclitaxel prevented tumor initiation, while paclitaxel alone did not reduce tumor initiation, suggesting that treatment with a FAK inhibitor could effectively eliminate tumor initiating CSCs. In summary, our data indicate that defactinib preferentially targets cancer stem cells and enhances the activity of paclitaxel in preclinical models of ovarian cancer. These results provide additional support for the current clinical development of defactinib in combination with paclitaxel for the treatment of ovarian cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C271. Citation Format: Christian M. Vidal, Vihren N. Kolev, Quentin G. Wright, Winnie F. Tam, David T. Weaver, Mahesh V. Padval, Qunli Xu, Jonathan A. Pachter. FAK inhibitor defactinib (VS-6063) enhances the efficacy of paclitaxel and preferentially targets ovarian cancer stem cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C271.