The RTK inhibitor, ABT-869 alone or in combination with various cytotoxic therapies demonstrate significant tumor growth inhibition in orthotopic hepatocellular carcinoma, renal cell carcinoma and prostate xenografts

C201

The RTKI, ABT-869, is a potent inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors and is currently in Phase 1 clinical trials. It exhibits potent inhibition of mutant kinases, such as fms-like tyrosine kinase 3 (FLT3), c-kit (CD117) and colony stimulating factor-1 receptor (CSF1R). Hepatocellular carcinoma (HCC), renal cell carcinoma (RCC) and prostate carcinoma (PC) are known hypervascularized/angiogenic tumor types. The vascular process in HCC tumor progression, VHL deletion-mediated HIF induction of VEGF in many RCCs, as well as PDGF expression in PC, highlight the potential of antiangiogenic therapy as an attractive therapeutic strategy. In this study, the therapeutic effect of the antiangiogenic agent, ABT-869 (alone or in combination with cytotoxic therapy) was assessed in HCC (HepG2, Hep3B, HUH7-LOT and rat H-4II-E), RCC (SN12-C), and PC (PC3M-Luc) implanted orthotopically in scid mice. HCC cells were injected into the left lobe of the liver, RCC cells in the renal subcapsule and PC cells in the dorsolateral lobes of the prostate. Sentinel mice were used to monitor tumor growth orthotopically prior to initiation of treatment except for PC3M-Luc where in vivo bioluminescence was measured to size-match groups prior to treatment and to monitor tumor growth. In all studies, ABT-869 was well tolerated alone or in combination with no exacerbation of toxicity of the cytotoxic agent as assessed by gross observations of body weight loss, dehydration, lethargy and moribund state, etc. Significant antitumor efficacy (percent tumor growth inhibition, TGI%) was observed with ABT-869 when administered at 25 mg/kg/day, p.o., b.i.d.x7-22: Hep3B (95%), HuH7-LOT (86%), HepG2 (70%) and rat H-4II-E (74%). In addition, combination therapy was significantly better than either agent alone. Cytotoxic compounds were assessed as monotherapy or in combination with ABT-869 in select models: rapamycin + ABT-869 (89%) vs. rapamycin (67%) and ABT-869 (56%) in SN12C and paclitaxel + ABT-869 (85%) vs. paclitaxel (60%) and ABT-869 (52%) in PC3M-Luc. Thus, the ability of ABT-869 (alone or in combination), to inhibit tumor growth in known hypervascular/angiogenic tumors suggests on-mechanism activity. Immunohistochemical and protein array analysis for phosphorylated RTK expression is being evaluated to delineate the potential underlying mechanisms of ABT-869 antitumor efficacy in these orthotopic models. These studies demonstrating the significant activity in a variety of orthotopic models may identify not only additional tumor types but also potential cytotoxic combination strategies to further the clinical development of ABT-869.