Abstract 774: Cabozantinib, a multi-target receptor tyrosine kinase inhibitor, decreases tumor growth and angiogenesis in a patient-derived dedifferentiated liposarcoma xenograft

Abstract

Background: Upregulation of receptor tyrosine kinase signaling pathways, including vascular endothelial growth factor receptor (VEGFR) and MET (also known as hepatocyte growth factor receptor), is found in different subtypes of soft tissue sarcoma. Cabozantinib (CABO) is a multi-target inhibitor of receptor tyrosine kinases including VEGFR, MET, RET, and KIT. We aimed to evaluate the anti-angiogenic and anti-tumor effect of CABO alone and in combination with the standard-of-care cytotoxic agent doxorubicin (DOX) in a patient-derived xenograft model of dedifferentiated liposarcoma (DDLPS). Methods: NMRI nu/nu mice were bilaterally transplanted with human UZLX-STS3 DDLPS tumors, a model originating from a patient with DDLPS. Twenty eight tumor-bearing mice were assigned to 4 groups and treated for three weeks with either vehicle (control), DOX (i.p., 1.2mg/kg/twice per week), CABO (p.o., 30mg/kg/QD) or CABO+DOX (same dose/schedule as for the single agents). Tumor volume was measured three times a week. Mitotic and apoptotic activity were assessed on hematoxylin and eosin (H&E) staining and with phospho-histone H3 (pHH3) and cleaved-caspase 3 (CC3) immunostainings. Microvascular density (MVD) was evaluated by counting CD34 positive vessels. Statistics were calculated using the Mann-Whitney U pairs tests. p < 0.05 was considered as statistically significant. Results: A significant delay in tumor growth was observed in CABO and CABO+DOX treated groups as compared to controls (p<0.05) or DOX single agent (p<0.05). Both CABO and CABO+DOX reduced the mitotic activity in comparison with control (38% and 66% decrease, respectively, p<0.005). CABO+DOX showed better antimitotic activity than either single agent DOX or CABO (p<0.005 for both). The CABO-based treatments induced higher apoptotic activity as compared to control (2.1 fold in CABO and 2.4 fold in CABO+DOX, p<0.005). Results were confirmed by pHH3 and CC3 stainings. Furthermore, significantly decreased MVD was observed in the CABO and the combination treated tumors as compared to control (64% and 67% decrease, respectively, p<0.005) and as compared to DOX alone (57% and 61% decrease, respectively, p<0.005). Conclusions: CABO has anti-tumor activity in the UZLX-STS3 DDLPS xenograft model by inhibiting proliferation, inducing apoptosis and suppressing angiogenesis. These in vivo results support ongoing and planned clinical trials with cabozantinib in mesenchymal malignancies. Citation Format: Haifu Li, Agnieszka Wozniak, Karel Van Den Bossche, Thomas Van Looy, Jasmien Wellens, Daphne Hompes, Dana Aftab, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. Cabozantinib, a multi-target receptor tyrosine kinase inhibitor, decreases tumor growth and angiogenesis in a patient-derived dedifferentiated liposarcoma xenograft. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 774. doi:10.1158/1538-7445.AM2015-774