Abstract 621: Targeting phosphatidylserine to improve androgen deprivation therapy of prostate cancer

Abstract

Abstract Androgen deprivation therapy (ADT) is effective against androgen-dependent prostate cancer, but patients usually relapse from the outgrowth of androgen-independent disease. Here, we tested the hypothesis that relapse can be prevented by combining ADT with treatment with a monoclonal antibody that binds exposed phosphatidylserine (PS). The rationale behind this hypothesis is that ADT will create hypoxia which induces PS exposure on the tumor vascular endothelial cells, leading to immune cell attack on tumor vasculature, collapse of the vessels and death of hormone-resistant and hormone-sensitive tumor cells through deprivation of oxygen and nutrients. In addition, the antibody should block the immunosuppressive effects of PS and induce reactivation of T-cell immunity. To test this hypothesis, we used ADT and anti-PS antibodies (2aG4 or murine chimeric 1N11) to treat mice bearing hormone-sensitive prostate tumors. The tumor models were: i) immunocompromised mice bearing human LNCaP prostate tumors; ii) transgenic (TRAMP) mice which spontaneously develop adenocarcinoma of the mouse prostate. Castration induced exposure of PS on blood vessels and tumor cells in both models. Vascular PS exposure corresponded with hypoxia, as judged by pimonidazole staining. In the LNCaP model, castration alone delayed tumor growth but all animals relapsed with hormone-independent disease, whereas mice treated with castration plus anti-PS antibody did not relapse. In TRAMP mice castrated at 15-weeks of age, only 54% (7/13) of mice treated with castration alone survived beyond 40-weeks of age, as compared with 92% (12/13) of mice treated with castration and 1N11. No toxicity to the mice was caused by the antibody treatment. Tumor blood flow and perfusion were markedly reduced in mice treated with castration and anti-PS antibody. Histological studies revealed extensive disruption of tumor vasculature and abundant infiltration of immune cells, principally M1 macrophages. These results demonstrate that PS becomes exposed on prostate cancer tumor vasculature and tumor cells in response to hypoxia caused by ADT in the tumor microenvironment. The exposed PS could serve as a target to enhance the efficacy of ADT against prostate cancer. 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 621. doi:10.1158/1538-7445.AM2011-621