Abstract 3289: PTX-008, a dual inhibitor of angiogenesis and tumor cell proliferation, potentiates the antineoplastic activity of targeted therapies in human tumor models
Authors: Bonezzi Katiuscia , Frapolli Roberta , Sala Federica , Astorgues-Xerri Lucile , Serova Maria , Raymond Eric , Cvitkovic Esteban , Noel Kay , Ubezio Paolo , Zucchetti Massimo , D'Incalci Maurizio , Giavazzi Raffaella , Taraboletti Giulia 
Published: June 2012

Abstract
PTX-008 is a non-peptidic topomimetic of anginex, a galectin-targeting peptide inhibitor of angiogenesis. This study was designed to investigate the antiangiogenic and antineoplastic activity of PTX-008 in vitro and in tumor models in vivo.
In vitro, PTX-008 affected endothelial cell (HUVEC) functions relevant to angiogenesis, including proliferation, motility, invasiveness, the formation of capillary like structures on Matrigel and adhesion to extracellular matrix components. The inhibitory effect, unrelated to the angiogenic factor (VEGF or FGF-2) was concentration dependent, with IC50 values in the low micromolar range. Tumor cell proliferation in vitro was also inhibited by PTX-008, with marked differences in sensitivity among tumor lines (IC50 from 1 to 190 µM).
In vivo, the antineoplastic activity of PTX-008 was tested on murine and human tumor models. PTX-008, administered i.p. at 10mg/kg or p.o. at 30 mg/kg, delayed the subcutaneous growth of B16-BL6 murine melanoma. PTX-008 (i.v. at 2 or 5 mg/kg, every other day for 3 weeks) was active in inhibiting the growth of the human ovarian carcinoma 1A9, but less effective on the human glioblastoma U87MG, highly expressing galectin-1. Pharmacokinetic analysis and in vitro experiments were used to investigate the mechanism of the observed difference in activity between the two tumor models. Plasma and tumor levels of PTX-008 were compatible with the observed in vitro activities. In particular, the tumor levels were compatible with the activity of PTX-008 on the highly sensitive 1A9 cells, suggesting that a direct antiproliferative effect on the tumor cells contributes to the antineoplastic activity of PTX-008 in vivo. PTX-008 potentiated the activity of the tyrosine kinase inhibitor sunitinb in vivo, in the 1A9 model. In vitro, it potentiated the antiproliferative activity of sunitinib on both endothelial cells (synergistic activity) and 1A9 cells (additive activity) indicating that the PTX-008/sunitinb combination in vivo effectively targets both the tumor and vascular compartments. PTX-008 potentiated the in vitro activity of sunutinib also on other tumors (SQ20B, HT29, Colo205, and the PTX-008 resistant HEP2), with synergistic or additive effects depending on the schedule of administration (sequential v.s. concomitant exposure). Interestingly, PTX-008 potentiated also the activity of another TK inhibitor, imatinib, on SQ20B and HEP2. In conclusion, PTX-008 – alone or in combination with tyrosine kinase inhibitors – has antineoplastic activity on selected tumor models through a dual activity on both endothelial and tumor cells. Schedule and sequence of administration are foreseen as critical factors in optimizing the use of PTX-008 in combination therapies.
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 3289. doi:10.1158/1538-7445.AM2011-3289