Abstract 2574: Striking activity of E-3810 combined with paclitaxel and 5FU in the triple negative breast cancer model MDA-MB-231
Authors: Damia Giovanna , Bello Ezia , Colella Gennaro , Berndt Alexander , D'Incalci Maurizio , Cavalletti Ennio , Camboni Gabriella 
Published: June 2012

Abstract
E-3810 is a novel small molecule that selectively inhibits VEGFR-1, -2 and -3 and FGFR-1 tyrosine kinases with IC50 &lt;30nM; at higher nM concentrations it also inhibits FGFR-2. We have previously shown that the compound has a strong anti-angiogenic effects in vivo and displays potent antitumour activity in all the human xenograft models in which it has been tested. The compound is currently undergoing a Phase 1 clinical trial in Europe. To better characterize its pharmacological profile, combination studies with paclitaxel (PTX) and 5-Fluorouracil (5FU) were performed in the triple negative breast cancer tumor MDA-MB-231. Nude mice were transplanted subcutaneously with 7×106 MDA-MB-231 cells. When tumors reached 400 mg, animals were randomized to receive vehicle, PTX i.v. (20 mg/kg Q7×3), 5FU i.v. (100 mg/kg Q7×2), E-3810 p.o. (20 mg/kg daily for 30 days), the combination of PTX plus E-3810 and 5FU plus E-3810. Efficacy of the treatments was expressed as best tumor growth inhibition and tumor regression. The PTX combination regimen appeared as tolerated as the treatment with the two single agents (body weight loss less than 15% in the PTX+E-3810 group). The 5FU containing regimen resulted instead in enhanced toxicity with a remarkable weight loss (more than 20%) and 5/8 toxic deaths (as opposed to 1/8 in the group treated with 5FU only). 5FU as single agent had only a modest effect on MDA-MB-231 tumor growth, while PTX and E-3810 as single agents showed a good antitumor activity, with growth inhibition resulting in tumor stabilization. Outstanding activity with complete tumour regressions was observed in mice receiving the combination regimens: 7/8 and 2/3 complete regressions in the group treated with E-3810+PTX and with E-3810+ 5FU respectively at 150 days after tumor transplantation. In vitro, cytotoxic studies showed no synergistic activity when MDA-MB-231 cells were treated with E-3810 and the two drugs, suggesting that host mediated mechanisms are at the basis of the tumor cures observed in the in vivo model. Further experiments are undergoing to optimize the 5-FU+E3810 schedule and to investigate if the use of E-3810 in combination can modify drug pharmacokinetics. Moreover, the degree of apoptosis, necrosis, proliferation, ERK phosphorylation and CD31 and collagen IV positivity in tumors induced by the single agents and the combination treatments will be assessed and compared. in order to clarify the mechanism of the observed striking antitumor activity. These data suggest that E-3810 can be combined with anticancer agents with different mechanisms of action and that that the combinations can cure tumor-bearing mice, opening up the way to a possibly effective new clinical combinations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2574. doi:10.1158/1538-7445.AM2011-2574