Abstract 1548: PTX-008, a designed mimetic of anginex, potentiates the effects of the VEGFR/PDGFR inhibitor sunitinib
Authors: LUCILE ASTORGUES-XERRI, Maria SEROVA, Sophie DENEUVE, Sebastien ALBERT, Marie-Paule SABLIN, Ivan BIECHE, Patrice HERAIT, Esteban Cvitkovic, Kay NOEL, Eric RAYMOND, Sandrine FAIVRE
Journal: Cancer Research (2010)

Abstract Background. Sensitivity to targeted agents inhibiting VEGFR/PDGFR signaling, including sunitinib, may be dependent of the concomitant modulation of alternative survival pathways. The lectin galectin-1 (gal1) is overexpressed in several tumors, selectively binds neuropilin-1 and enhances VEGFR2 signaling thereby activating the MAPK and/or AKT pathways in cancer cells. Those effects may result in modulation of cancer cell proliferation, apoptosis, cell cycle, and tumour angiogenesis. Optimizing the inhibition of gal1/neuropilin-1/VEGFR-dependent signaling may be a useful approach to improve the activity of multitargeted drugs in cancer cells. The aim of the present study was to evaluate the effects of PTX-008, a novel drug that targets gal1, alone or in combination with sunitinib on several human cancer cell lines. Material and Methods. Antiproliferative effects were evaluated in human colon, breast, ovarian, head &amp; neck, lung, prostate and HCC cancer cell lines by MTT assay. Effects of PTX-sunitinib combinations were determined by median effect plot analysis (Chou &amp; Talalay). Results. Antiproliferative effects of sunitinib as single agent were evaluated on a panel of 20 human cancer cell lines including SQ20B, COLO205 and HT29 with IC50=2; 3 and 8µM, respectively. Antiproliferative effects of single agent PTX-008 were detected in several cell lines including head &amp; neck SQ20B, colon HT29 and COLO205, lung HOP62 and ovarian cancer cells OVCAR3 and IGROV1 with GI50 of 3; 9; 9; 27; 3 and 27µM respectively. In contrast, head &amp; neck HEP2, prostate DU145, breast MCF7 and SKBR3, renal CAKI1, hepatocarcinoma SK-HEP1 and colon HCC2998 lines appear to be resistant to PTX-008 (GI50&amp;gt;27µM). Effects of PTX-008 were slowing cell proliferation and G2/M accumulation, along with blockage of ERK and AKT survival pathways. In order to evaluate the effects of PTX-008 in combination with other multitargeted inhibitors, we used sequential and simultaneous exposure to PTX-008 with sunitinib. Combinations of PTX-008 with sunitinib in two colon cancer cell lines COLO205 and HT29 (which express low gal1, VEGFR and PDGFR mRNA), result in additive (CI=1) and synergistic (CI&amp;lt;1) effects respectively, regardless of the sequence schedule. In SQ20B, a highly PTX-008 sensitive cell line expressing low gal1, VEGFR and PDGFR mRNA, and in HEP2, a PTX-008 resistant cell line which express high gal1 but low VEGFR and PDGFR mRNA, PTX-008 given simultaneously with or after sunitinib resulted in at least additive effects. When the cells were exposed to PTX-008 prior to sunitinib, synergy was observed. Studies on cell cycle and signalling are ongoing. Conclusion. Combination of PTX-008 with sunitinib appears to be synergistic both in PTX-008-sensitive and -resistant cells, suggesting that modulation of gal1 signaling may be used to enhance the activity of sunitinib. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1548.