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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

e13528 Background: Analysis of primary clinical specimens of DDLPS revealed evidence of AKT activation in 27% of cases (Gutierrez A, et al. Aberrant AKT activation drives well-differentiated liposarcoma. PNAS 2011; 108(39):16386-91). We evaluated the efficacy of the PI3K inhibitor GDC-0941 (GDC) alone and in combination with doxorubicin (DOX) in patient- and cell-line derived DDLPS xenografts with proven PI3K/AKT pathway activation. Methods: NMRI nu/nu mice were either injected bilaterally with 1x107SW872 cells or transplanted with human DDLPS (UZLX-STS3). Animals were randomized to 4 groups (6 mice/group) and treated for two weeks: vehicle, DOX (i.p., 1.2mg/kg/biw), GDC (p.o., 75mg/kg/qd), GDC+DOX (same dose/schedule as single agents). Efficacy was assessed by tumor volume assessment, Western blotting and histological evaluation (H&E). Mitotic and apoptotic effects were confirmed using immunostainings for phospho-histone H3 (p-H3) (for proliferation), and cleaved caspase 3 (CC3) (for apoptosis). Results: GDC and GDC+DOX significantly delayed the growth of both xenografts (74% decrease under GDC and 77% under GDC+DOX in SW872, 67% under GDC and 56% under GDC+DOX in UZLX-STS3, vs. control). GDC and GDC+DOX treatment resulted in reduced mitotic activity and increase in apoptosis, as compared to untreated tumors in both models (Table). The activation of PI3K signaling was nearly completely suppressed in the GDC and GDC+DOX treated groups in SW872, whilea weak activation of the pathway was still observed in UZLX-STS3. Conclusions: GDC-0941 has anti-tumor activity, decreases tumor proliferation and induces apoptosis in DDLPS with PI3K/AKT activation. The GDC+DOX combination did not show additive effect in vivo. [Table: see text]