Preclinical development of an interleukin-11 receptor-targeted pro-apoptotic peptide against advanced prostate cancer

Abstract

3190 Background: Direct screening of combinatorial peptide libraries in patients allows the identification of ligands that target biochemical differences in the endothelium of blood vessels. In a screening performed on a patient, we selected and isolated a mimic motif of interleukin 11 (IL-11) from prostate biopsies after an intravenous administration of a phage display peptide library. We also demonstrated that the IL-11 phage mimic bound specifically to a corresponding IL-11 receptor (IL-11Rα). More recently we showed that IL-11Rα is a potential target for intervention in human prostate cancer (PCa) through morphologic and functional analyses (Zurita et al., Cancer Res 2004, in press). We observed stage-specific up-regulation of IL-11Rα during disease progression, particularly in androgen-independent and metastatic PCa and their associated blood vessels. Moreover, a pro-apoptotic peptide was specifically targeted and internalized through IL-11Rα in PCa cell lines. Here we evaluate antitumor efficacy, selectivity of action, and host toxicity in preclinical animal models of human PCa. Methods: We are currently performing systemic efficacy studies in nude mice PCa xenograft models, and dose range-finding studies to establish a maximally tolerated dose in mice. Results: Our preliminary data show promising results against PCa xenografts in nude mice. Conclusions: An IL-11Rα-targeted, chimeric pro-apoptotic peptide, is a candidate for translation into clinical applications. No significant financial relationships to disclose.