Combination Of Ctx-0294945 A Highly Selective Inhibitor Of Focal Adhesion Kinase With Bevacizumab In Pre-Clinical Models Of Breast Cancer

Abstract Background: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that provides a critical hub for signalling from at least four different classes of cellular sensing mechanisms including growth factor receptors, GPCRs, integrins and mechanical stress forces. By temporal and spatial integration of signals from these sources, FAK plays a central role in cell migration, invasion and proliferation; processes vital for tumorigenesis. The significance of FAK to the function of signal transduction pathways provides a strong rationale for the combination of FAK inhibitors with other targeted agents to achieve improved efficacy against a range of cancers. Others have demonstrated the importance of FAK in angiogenesis and therefore combining a FAKi with anti-VEGF agents is attractive as it employs two complementary mechanisms of suppressing the formation of tumor vasculature. Here we present results from the co-administration of CTx-0294945, a highly selective FAKi, and bevacizumab (bev) in an orthotopic model of human breast cancer. Methods and Results: CTx-0294945 is an orally bioavailable small molecule ATP competitive inhibitor of focal adhesion kinase (FAK KD=0.21 nM). It exhibits high selectivity against a diverse panel of 125 kinases including the closely related Pyk2. CTx-0294945 inhibits autophosphorylation of 397Y-FAK in MDA-MB-231 cells with an IC50 = 7 nM and exhibits low general cellular toxicity (IC50 = 2.7 µM, MDA-MB-231 cells). CTx-0294945 is suitable for oral administration (%F=58 and t1/2=5.1 h at 20 mg/Kg in rat) and does not inhibit (IC50 >20 µM) any of the cytochrome p450 isoforms tested to date. To assess the co-administration of CTx-0294945 with bev, mice were injected orthotopically with MDA-MB-231 cells (106). After 14 days, when tumors were palpable, mice were randomized into 4 groups and dosing commenced. The groups were treated with CTx-0294945 (80 mg/kg QD, PO), bev (12.5 mg/Kg IP, x2/week), CTx-0294945 (80 mg/Kg QD, PO) and bev (12.5 mg/Kg IP, x2/week) or vehicle. Tumor growth was monitored and on day 28 animals in the vehicle and CTx-0294945 arms were culled when the size of the tumors reached ethical end point (1000 mm3). Tumor growth in the bev only and the CTx-0294945 + bev arms was significantly inhibited (75% and 88% TGI respectively). At this time the treatment regimes for both cohorts were stopped and tumor growth allowed to progress. After an additional 14 days the experiment was terminated when the bev treatment group reached ethical end point; however the average size of the tumors in the CTx-0294945 + bev cohort was still was only 562 mm3. Conclusions: Our data suggest the potential utility of combining a selective FAK inhibitor with bevacizumab to prevent tumour progression and enhance the durability of response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-308. doi:1538-7445.AM2012-LB-308