Prostate cancer is the most common malignancy in North American men. While patients have benefited from advances in androgen deprivation therapy, prostate cancer ultimately evolves to a metastatic or castrate-resistant state that makes it the second-leading cause of cancer mortality in males. In the past 3 years, new chemotherapeutic drugs with efficacy in advanced disease have been introduced. Yet their efficacy is limited by dose-limiting toxicities and side effects due primarily to suboptimal biodistribution - they do not target tumors directly. To overcome these limitations, we have developed a novel drug encapsulation system for efficient and specific delivery of chemotherapeutic agents to prostate tumors. The reptilian reovirus-derived fusion-associated small transmembrane (FAST) protein (p14) increases the fusion of liposomes to cell membranes. In this study, we combine these fusogenic liposomes with peptides targeted to gastrin-releasing peptide receptors (GRPR) to improve the delivery of chemotherapeutic payloads specifically to prostate cancer cells while sparing normal tissue.
A fusion protein containing p14 and a C-terminal bombesin peptide was produced in a baculovirus expression system and incorporated into liposomes. The targeting and fusogenic properties of the p14-bombesin protein-containing liposomes were confirmed using flow cytometry. These experiments demonstrated improved delivery to cancer cells in vitro (PC3, LNCaP), compared to non-tumoral cells (BPH). The specificity of targeted fusogenic liposomes was confirmed by knockdown of GRPR and by blocking with free bombesin peptides. We then used intravital imaging in an avian xenograft model to measure the accumulation and specific uptake of the fusogenic targeted liposomes in prostate tumors compared to benign (BPH) and normal tissue, and found a significant increase in uptake in GRPR-expressing prostate cancer tumors using the bombesin-targeted fusogenic liposomes compared to controls. As a further proof of principle, we modified a commercial formulation of Doxil to incorporate our p14-bombesin fusion protein. This formulation showed significantly enhanced cancer-specific cytotoxicity in vitro and increased efficacy in xenograft models.
Taken together, these studies demonstrate that molecular-targeted fusogenic FAST liposomes are a promising platform for improving the efficacy of chemotherapies that should show enhanced activity in advanced and metastatic prostate cancers.
Citation Format: Jihane Mriouah, Rae-Lynn Nesbitt, Desmond Pink, Roy Duncan, Andries Zijlstra, John D. Lewis. Fusogenic liposomes: A novel therapeutic strategy to efficiently target and destroy prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 821. doi:10.1158/1538-7445.AM2014-821