Abstract 4520: Targeting galectin-1 with PTX-008 inhibits invasion, tumor growth and metastasis in human carcinoma models

Abstract

Abstract Background. Galectin-1 belongs to a phylogenetically conserved family of carbohydrate binding lectins (galectins) that share a conserved carbohydrate recognition domain and are involved in tumor growth and metastasis. The aim of this study was to evaluate the effect of galectin-1 inhibition by shRNA or PTX-008, a topomimetic of antiangiogenic drug Anginex, on in vitro cancer cells invasion and on in vivo tumor growth and metastasis development. Material and Methods. In vitro invasion was evaluated using Matrigel assay. Transfection of SQ20B head&neck cancer cells with galectin-1 shRNA was done using the Santa Cruz Biotechnology protocol. In xenograft studies, cells were injected s.c. into female nu/nu athymic mice either treated with vehicle or 10mg/kg PTX-008 i.p. daily for 3 weeks. Measurements were done twice a week, tumor volume was determined as 3.14(width2)/length. Results. PTX-008 demonstrated potent antiproliferative effects on galectin-1 expressing SQ20B cells with IC50 of 3.8µM. Transfection of SQ20B cells with shGal1 (SQ-shGAL1) did not change proliferation of cells. In contrast, shGAL1 and PTX-008 significantly decreased invasion in matrigel assays. SQ20B and SQ-shGAL1 cells were injected in nude mice and SQ20B mice were treated continuously with PTX-008. Targeting galectin-1 with PTX-008 as well as inhibiting endogenous galectin-1 by shRNA inhibited significantly tumor growth in mice. Similar results with inhibition of tumor growth were obtained using A2780-1A9 ovarian xenografts treated with 5 and 10 mg/kg PTX-008. Subcutaneous injections of SQ20B in mice result in the development of multiple subcutaneous metastases. Interestingly, PTX-008 treated SQ20B-xenograft mice and mice with SQ-shGAL1 implanted tumors had respectively 80% and 50% decreased numbers of secondary tumors as compared to control groups. After treatment, tumors were isolated and analyzed for expression of galectin-1 by RT-PCR and western blot analysis. Interestingly, treatment with PTX-008 seems to inhibit the protein level of galectin-1 in SQ20B xenografts. In addition, tumors treated with PTX-008 expressed lower VEGFR2 and CXCR4 mRNA levels as compared to control tumors, suggesting antiangiogenic properties of PTX-008. The study of molecular mechanisms implicated in galectin-1-induced inhibition of tumor growth and metastasis development is in progress. Conclusion. Our findings suggest that targeting galectin-1 by PTX-008 may be an effective approach to treat cancer patients and to prevent secondary tumor development. 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 4520. doi:10.1158/1538-7445.AM2011-4520