Abstract 1618: Combination of axitinib and crizotinib in renal cell carcinoma models.

Abstract

Abstract Background: The vascular endothelium growth factor (VEGF) pathway plays a pivotal role in angiogenesis. Axitinib (AG-013736), a potent small molecule receptor tyrosine kinase inhibitor highly selective for VEGF receptor 1, 2 and 3, is currently being tested in Phase II/III clinical trials for the treatment of solid tumors and has been approved as a second-line treatment for renal cell carcinoma (RCC). The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) pathway has also been shown to play an important role in tumor vascularization, as well as epithelial to mesenchymal transition (EMT), metastatization, and acquired resistance. Crizotinib (PF-02341066), a potent and selective inhibitor of anaplastic lymphoma kinase (ALK) and c-Met kinase, has been approved for the treatment of advanced ALK-positive non-small cell lung cancer. The aim of this study was to assess the combinational effect of axitinib and crizotinib in two models of RCC with differing degrees of c-Met expression and sensitivity to anti-angiogenic agents. We hypothesized that the combination would provide greater anti-tumor and anti-angiogenesis efficacy compared to single-agents. Methods: Human high c-Met expressing 786-O and low c-Met expressing RP-01 (developed from a skin metastasis of a patient with sporadic clear cell RCC) xenografts were inoculated into SCID mice (8/group). After approximately 6 weeks of tumor growth, mice were treated with vehicle, axitinib (36 mg/kg, 2x/day, oral gavage), crizotinib (25 mg/kg, 1x/day, oral gavage), or axitinib plus crizotinib. Once tumor volume of vehicle mice reached 200 mm2, mice were sacrificed and tumor tissue was excised and analyzed. A sunitinib-resistant RP-01 model was also developed through continued in vivo exposure to sunitinib (60 mg/kg, 1x/day, oral gavage) to further test the different responses to treatments and to evaluate the possible role of c-Met in sunitinib resistance. Compounds were kindly provided by Pfizer. Results: We observed that single-agent crizotinib anti-tumoral activity was strongly related to c-Met expression, inhibiting 786-O tumor growth in vivo, but not RP-01. More interestingly, significant synergistic effects were found with crizotinib and axitinib, whereby enhanced inhibition of 786-O xenograft tumor growth was found (from 17%, axitinib, to 76% combination, p <0.05 of combination vs. both single agents). No overt signs of toxicity were observed in any of the experimental groups. Vessel density, pericyte coverage (CD31 and NG2), and EMT markers are being evaluated with immunohistochemistry. Results from combination treatment in the sunitinib-resistant model will be presented. Summary: Overall, the data demonstrate that this combination therapy resulted in significant anti-tumor activity in a high c-Met expressing RCC model, highlighting the potential therapeutic application of combined VEGF and c-Met blockade in the treatment of RCC. Citation Format: Eric S. Ciamporcero, Kiersten M. Miles, Remi Adelaiye, Stefania Pizzimenti, Giuseppina Barrera, Roberto Pili. Combination of axitinib and crizotinib in renal cell carcinoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1618. doi:10.1158/1538-7445.AM2013-1618