Abstract 2076: Albumin-linked proaerolysin based molecular grenades: A systemic therapeutic for disseminated castration resistant prostate cancer

Abstract

Abstract The progression of prostate cancer (PCa) to metastatic castration resistant prostate cancer (CRPC) is an ominous clinical finding that is a significant therapeutic challenge for clinicians. Current treatments for men with CRPC are not curative and only extend survival for a little more than 12 months. Conventional anti-cancer therapies induce death of cancer cells by exploiting the relatively fast rate of growth cancer cells display in relation to normal cells. Radiation and chemotherapeutics are designed to arrest replication of the tumor DNA. The dose limiting toxicities associated with various anti-cancer therapies, is thought to play a role in tumors acquiring resistance to conventional therapeutics (chemoresistance). To overcome the adverse side effects of conventional anti-cancer therapies, the Isaacs laboratory has advocated the use of chemical engineering principles to modify potent killing toxins to produce “molecular grenades.” These molecular grenades are selectively “detonated” by the prostate tumor; thereby, liberating their killing toxin efficiently only within the immediate environment surrounding cancer sites. The objective for this project is to use a bio-engineering approach to produce recombinant pro-toxins designed for specific cleavage by a defined protease whose high expression is restricted to the tumor microenvironment at sites of metastatic CRPC. In contrast to benign tissue, where the vasculature is only permissive to the diffusion of micromolecules across the endothelial barrier, the leaky nature of the tumor vasculature allows for macromolecules to pass this barrier as well. Human serum albumin (HSA) is a large macromolecule, which will aid in the targeted delivery of the toxin, proaerolysin (PA), to malignant sites via the enhanced permeability and retention (EPR) effect. We are able to produce a recombinant HSA linked to the N-terminus of Proaerolysin (HSA/PA) via a peptide linker specific for the protease prostate specific antigen (PSA). This recombinant HSA/PA shows selective activation in the presence of PSA expressing PCa cell lines with toxicity at low nanomolar concentrations. The PA toxin is extremely toxic when intravenously (IV) injected in mice, displaying an LD100 of 100ng. Restricting the potent killing ability of PA to sites of PCa is key, so that it can be delivered as a systemic therapeutic. Linking HSA with PA to produce the recombinant HSA/PA has neutralized the extreme toxicity observed when PA was injected directly in mice. With the recombinant HSA/PA we can safely dose mice up to 12ug. The characteristics of the prostate tumor microenvironment show promising potential for preventing chemoresistance and death from metastatic disease by lending itself to therapeutic targeting with our molecular grenade Proaerolysin. . Citation Format: Freddie L. Pruitt, Nathaniel Brennen, Lizamma Antony, David M. Rosen, Samuel Denmeade, John Isaacs. Albumin-linked proaerolysin based molecular grenades: A systemic therapeutic for disseminated castration resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2076.