The Anti-Tumor Effect of Motesanib in Pre-Clinical Models of Human Basal-Like Breast Cancer.

Abstract

Abstract Background: Growth of breast cancer is dependent upon sustained angiogenesis, of which vascular endothelial growth factor (VEGF) is a major stimulant. Increased expression of VEGF in breast cancers is associated with poor prognosis and disease recurrence, and anti-angiogenic agents are being developed as potential new therapies. Motesanib is an oral inhibitor of VEGF receptors 1, 2 and 3, platelet-derived growth factor receptor, and stem cell factor receptor (c-Kit). This study determined the effects of motesanib on the growth of human basal-like breast cancer cell lines in immunodeficient mice, alone and in combination with paclitaxel.Materials and Methods: Breast cancer cells BT-549 and GILM2 were injected into the mammary fatpad (MFP) of mice; HCC1187 cells were injected on the subcutaneous flank. Mice with established tumors (150-200 mm3) received motesanib orally BID, at 7.5, 25 or 75 mg/kg for three weeks. Tumors were collected for analysis of blood vessels (CD-31 staining), viable tumor area, and for markers of proliferation (Ki67) and apoptosis (cleaved caspase-3). GILM2 cells were injected into the tibia of mice to model growth in bone; mice with GILM2 MFP or tibia tumors received motesanib (25 mg/kg BID) or paclitaxel (24 mg/kg Q4Dx5), or the combination. Intratibial GILM2 tumors expressing luciferase were monitored by bioluminescence and radiography to evaluate osteolysis. Analyses of tumor size were assessed by ANOVA, and immunohistochemical tests by Student's t tests.Results: Motesanib produced dose-dependent inhibition of growth of BT-549, GILM2 and HCC1187 tumors. All doses of motesanib significantly inhibited the growth of BT-549 tumors (>55% inhibition, P<0.01 vs. control). For GILM2 tumors, 25 and 75 mg/kg motesanib gave 47% and 58% growth inhibition, respectively (P<0.008), and for HCC1187, these doses produced 81% and 91% growth inhibition, respectively (P<0.001). GILM2 tumors from mice receiving >25mg/kg had smaller viable tissue areas (P<0.001), and fewer CD-31 positive blood vessels (P<0.001) than tumors from control mice. Immunostaining showed that 25mg/kg motesanib reduced proliferation of GILM2 tumors (P<0.001 vs. control), with no change in numbers of apoptotic cells. Treatment with 25 mg/kg motesanib or paclitaxel (24mg/kg Q4Dx5) significantly reduced GILM2 tumor burden in the MFP (46% and 49% inhibition, respectively) and in the bone (77% and 68% inhibition, respectively) (P<0.05 vs. control). Combining the agents did not enhance the anti-tumor effects of paclitaxel. Bioluminescent measurements and X-rays showed that motesanib alone was as effective as paclitaxel at reducing GILM2 growth and osteolytic destruction in bone (P<0.05, vs. control).Conclusion: Oral administration of motesanib significantly inhibited the growth of three ER-, PR- HER2-negative basal-like breast cancer cell lines in vivo. Motesanib was as effective as paclitaxel at controlling the growth of GILM2 in the MFP, and reduced osteolysis in bone tumors. These data suggest that motesanib has anti-angiogenic action in diverse tumor microenvironments. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5057.