Novel Methods of Targeting Protein Cytotoxins to Metastatic Prostate Tumors: Teaching "Old Proteins" New Tricks
Rogers, Oliver C.
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Prostate cancer is among the leading causes of cancer-related death in the United States with 30,000 people succumbing to the disease every year. A vast majority of these men, at the time of diagnosis, presented with distal prostate cancer as opposed to cancer that was contained within the primary organ. Currently, there is no cure for metastatic prostate cancer despite novel therapeutic advances which have been made over the last 15 years. Our lab is interested in molecular engineering strategies that selectively poison cancer cells but do not affect normal cells. Because a majority of prostate-derived tumors grow very slowly, traditional anti-proliferative cytotoxic chemotherapies are largely ineffective. Therefore, we have selected an array of cytotoxic agents that kill cells regardless of their stage in the cell cycle. These agents, Pro-aerolysin, Granzyme B, and Pseudomonas Exotoxin A, are all protein weapons found in nature that have evolved millions of years to efficiently kill eukaryotic cells. Because these weapons all must be regulated to prevent off-target toxicity, we propose to modify the regulatory steps involved in these toxins’ mechanisms in order to selectively kill prostate cancer cells. We aim to do this in a myriad of different ways using previously discovered modifications and mutations made to these agents which have been shown to modulate their activity. Specifically, we intend to engineer these toxins’ ability to bind to cells more selectively or to be activated by enzymes selective for the prostate cancer micro-environment. This work will specifically discuss the rationale behind each modification, demonstrate the synthesis and purification of each protein, and assess the biological activity of each in respect to prostate cancer. Ultimately, we hope that the lessons learned from this study will serve as a useful case study in biochemical engineering principles that can lead to novel therapeutic discoveries for the treatment of human disease.