293 Background: The systemic therapy of advanced UC has significant unmet needs. Angiogenesis appears to play a major tumorigenic role in UC, and inhibitors of the VEGF axis have demonstrated activity in clinical trials. Ang/Tie2 and FGFR1 are angiogenic pathways that may collaborate with the VEGF pathway to promote growth. Hence, we sought to examine the preclinical activity of CEP-11981, a small molecule inhibitor of Ang/Tie2, FGFR1 and VEGFR-1-2, in UC. Methods: The in vitro anti-tumor activity of CEP-11981 was evaluated in 4 human cell-lines (5637, TCC-SUP, RT4, RT112). In vivo examination of the anti-tumor activity of different doses of daily oral CEP-11981 for up to 4 weeks was examined in subcutaneous RT4 xenografts. Harvested xenograft tumors were subjected to immunohistochemistry (IHC) to evaluate apoptosis (cleaved-caspase [cc]-3) and angiogenesis (CD31). Results: In vitro activity was not detected at low micromolar concentrations in all 4 cell-lines (attainable in human subjects). Preliminary experiments suggested that both 5 mg/kg and 10 mg/kg orally once daily induced similar regressions of RT4 xenografts, which appeared greater than regressions with 2.5 mg/kg orally once daily. Given that the weight of mice was better maintained with 5 mg/kg dose, we performed the confirmatory experiment comparing placebo with CEP-11981 at 5 mg/kg orally once daily in RT4 xenografts. At this dose, CEP-11981 significantly arrested the growth of UC xenografts compared to control (p<0.05). IHC of harvested RT4 xenografts demonstrated numerically lower angiogenesis (p=not statistically significant) but no change in cc-3. Modulation of Tie2 is being examined. Conclusions: CEP-11981 demonstrated significant preclinical cytostatic anti-tumor activity against human UC xenografts in a murine model, which was attributable to inhibition of angiogenesis. Clinical development of CEP-11981 in tolerable combination regimens and the discovery of tumor and host related biomarkers predictive for benefit are warranted.
TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma