Antitumor Activity of Motesanib Alone and in Combination with Chemotherapy in Xenograft Models of Human Non-Small Cell Lung Cancer

Abstract Introduction: Angiogenesis is required for tumor growth. Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) play a critical role in the development of neovascularization. Motesanib is an orally administered small-molecule inhibitor of angiogenesis with direct antitumor activity, targeting VEGFR1, 2, and 3; platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor (c-kit). In this study, we examined the effects of motesanib in preclinical models of human non-small cell lung cancer (NSCLC), both as a single agent and in combination with docetaxel or cisplatin. Methods: The ability of motesanib to inhibit the growth of NSCLC cell lines in vitro was assessed using the ATPlite cell viability assay. Five human NSCLC cell lines were evaluated, including A549 (adenocarcinoma), Calu-6 (anaplastic carcinoma), NCI-H358 (bronchioalveolar carcinoma), NCI-H1299 (large cell carcinoma) and NCI-H1650 (adenocarcinoma). To determine in vivo efficacy, mice bearing established xenografts were treated orally with motesanib BID or QD at doses ranging from 7.5 to 75 mg/kg. For combination experiments, cisplatin (4 or 5 mg/kg) or docetaxel (5, 15 or 30 mg/kg) administered IP once weekly were given with motesanib. Tumors were collected for assessment of blood vessel area (anti-CD31 staining) and viable tumor area (hematoxylin staining). Tumor burden was calculated as the viable fraction multiplied by the respective terminal tumor weight. Results: Motesanib had no effect on the in vitro growth of any of the lung cancer cell lines tested (IC50 >5 µM). In contrast, treatment with motesanib in vivo resulted in a dose-dependent inhibition of tumor growth in all five lung cancer models. In combination studies, treatment with motesanib and cisplatin significantly enhanced (p <0.05) the antitumor activity in the NCI-H358, NCI-H1650, and Calu-6 xenograft models. Treatment with motesanib in combination with docetaxel significantly enhanced (p <0.05) the anti-tumor activity in the Calu-6 and A549 models, compared with either single agent alone. All treatments were well tolerated. The factors responsible for the differential sensitivity of these tumors to motesanib are currently being explored. Histological analyses of NCI-H358 tumors revealed a reduction in blood vessel area after treatment with motesanib alone and in combination with cisplatin, as well as a significant decrease in viable tumor burden after combination therapy (p <0.05). Together, these data suggest that motesanib prevented tumor growth by inhibiting angiogenesis, and combination of motesanib with chemotherapy resulted in a significantly enhanced reduction in tumor growth. Conclusion: The antitumor activity of motesanib in multiple preclinical models of NSCLC supports development of this antiangiogenic agent for the management of NSCLC in combination with standard of care chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1380.