Anti-Tumor Effects Of Dovitinib In Patient-Derived Gastrointestinal Stromal Tumor (Gist) Xenograft Models.

10532 Background: Advanced GIST is treated with the tyrosine kinase inhibitors imatinib, sunitinib and regorafenib, but the majority of patients develop heterogeneous resistance to these agents. In an attempt to overcome such resistance, we tested the efficacy of dovitinib which acts against VEGFR, FGFR, FLT3, PDGFRB and KIT, using patient-derived GIST xenograft models. Methods: NMRI nu/nu mice (n = 47) were transplanted bilaterally with the human GIST xenografts UZLX-GIST2 (KIT p.A502_Y503dup) or -GIST9 (KIT p.P577del+p.W557LfsX5+p.D820G) and were treated in 4 cohorts: control (untreated), imatinib (50 mg/kg/bid p.o.), imatinib (100 mg/kg/bid p.o.) and dovitinib (30 mg/kg/qd p.o.). Efficacy was assessed by tumor volume measurement (3x/week), histopathology, immunohistochemistry [Ki67, phospho-Histone H3 (pHH3), cleaved PARP] and Western blotting analysis of KIT signaling. Histologic response (HR) was graded according to Antonescu et al. Clin Cancer Res 2005; 11:4182-90. Microvascular density (MVD) was as...