Abstract 661: Efficiency of the multivalent pseudopeptide nucant 6L in castration- and chemo-resistant prostate cancers

Abstract

Abstract Introduction: Targeted therapies on advanced prostate cancer, resistant to castration and chemotherapy, offer significant hope for future treatments. NucAnt 6L (N6L) is a ligand of surface nucleolin. This protein is overexpressed at the cell surface of tumoral and endothelial cells, and is involved in tumor growth and associated angiogenesis. It has been demonstrated that N6L displays, in vitro and in vivo, a double anti-tumoral activity. It inhibits growth of various human tumor cell lines derived from mammary and colorectal carcinoma, melanoma, glioblastoma and lymphoma. In addition, it can compromise associated angiogenesis. In this context, N6L might be of value for therapeutic intervention. Previous studies have demonstrated drug's efficacy of this agent in prostate cancer cell lines. However, its effect on therapeutic resistant lines has yet to be documented. Using in vivo and in vitro models, the aim of this work is to evaluate N6L activity on castration and chemo-resistant prostate cancers. Methods: When maintained in medium deprived of androgens, androgen-responsive LNCaP cells undergo a “transdifferentiation” process giving rise to neuroendocrine (NE) like LNCaP cells which are resistant to androgen deprivation and chemotherapeutic agents such as docetaxel. Here, the anti-tumoral activity of N6L has been evaluated, in vitro, on human LNCaP-NE cells. Cell viability, as assessed by MTT test, and soft agar assays were performed at 72 hours after treatment with N6L (range of 0.1 to 100 µM). In vivo, anti-tumoral activity was then confirmed using VCaP ectopic xenografts into athymic nude mice, a condition that mimics clinical evolution of advanced prostate cancers in human. Mice bearing tumors of about 600 mm3 were castrated. Mice were treated with either vehicle or N6L at 10 mg/kg by the intraperitoneal route at different times of tumor growth. Tumors volumes were monitored at different time points using the caliper method. Results: N6L induces death of LNCaP-NE cells with a IC50 of 16.2 µM. These findings were supported by soft agar assays in which LNCaP-NE cells were found to be sensitive to N6L treatment whereas they were resistant to docetaxel. In vivo, N6L inhibits VCaP tumor growth at different stages of tumor progression, the castration-sensitive state and also the castration resistant state. Conclusions: N6L, which is currently in I/IIb phase of clinical trials, might represent a new targeted approach to treat advanced prostate cancers resistant to castration and chemotherapy. 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 661. doi:10.1158/1538-7445.AM2011-661