Abstract A14: A novel integrin-targeted therapeutic agent for prostate cancer with anti-tumor/anti-angiogenic activity

Abstract

Abstract Contortrostatin (CN), an anti-invasive/anti-angiogenic protein and member of the disintegrin family is a homodimeric protein that was isolated from southern copperhead snake venom. CN displayed potent antitumor activity against human prostate cancer (PC) xenografts in nude mice (The Prostate 70:1359, 2010). However, a major obstacle to the clinical translation of CN was the dependence on snake venom as the commercial source of the protein. To directly address this problem, we produced a recombinant version of CN, called vicrostatin (VCN), which is as active as native CN both in vitro and in vivo. The antitumor activity of VCN is based on its high affinity interaction with integrins αvβ3, αvβ5, and α5β1. These integrins are involved in invasion not only of cancer cells, but also of vascular endothelial cells. This diverse mechanism of action provides VCN with a distinct advantage over many other antiangiogenic agents, which act on a single angiogenic pathway. In our new studies using VCN as therapy for PC, we employed an intravenous (i.v.) delivery system using a neutral unilamelar liposome formulation, suitable for clinical use, to encapsulate VCN (LVCN). LVCN was found to have a circulatory half-life of ∼22 hours whereas unencapsulated VCN has a half-life of ∼30 minutes. An important feature in the design of VCN is a carboxylterminal sequence alteration that produces ∼13-fold higher affinity (as compared to CN) for integrin α5β1, which has been shown to be over-expressed on angiogenic endothelial cells and on PC cell lines. Based on our previous in vivo efficacy results with a liposomal formulation of CN in breast and prostate cancer, we hypothesized that i.v. delivery of LVCN should be clinically relevant and lead to passive accumulation of VCN in the tumor. The increased circulatory residence time provided by liposomal encapsulation is critical to the biological efficacy of LVCN; by comparison naked VCN at the same dose has very limited activity in cancer xenograft models. In an experimental bone metastasis model, CWR22 prostate cancer cells were injected into a drilled hole in one tibia of nude mice. LVCN was injected i.v. at 100μg per dose twice per week. LVCN showed ∼80% inhibition of tumor growth. Thus, i.v. liposomal delivery leads to accumulation of LVCN in the metastatic tumor bed in nude mice where the disintegrin exerts its potent anti-tumor and anti-angiogenic activity without apparent side effects or immune recognition. In conclusion, we have shown that a liposomal formulation of VCN exerts significant anti-tumor activity in an experimental bone metastasis model of PC. In future studies, we will examine combination therapy employing VCN and chemotherapy in xenograft and bone metastasis models of PC. Citation Format: Francis S. Markland, Jr., Jacek Pinski, Stephen Swenson, Qingcai Wang, Radu Minea. A novel integrin-targeted therapeutic agent for prostate cancer with antitumor/antiangiogenic activity [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A14.