Based upon substantial published literature from multiple groups, as well as unpublished studies to be presented from the applicants'laboratories, there is strong documentation that bone marrow-derived Mesenchymal Stem Cells are released into the blood stream and home to sites of primary and metastatic prostate cancer driven by the inflammatory microenvironment characteristically present within prostate cancer's stromal compartment. Thus, the hypothesis of this project is that allogeneic human bone marrow-derived MSCs (hbMSCs) can be used as a cell-based targeting vehicle to selectively deliver (i.e., home) therapeutic agents to sites of prostate cancer, thus sparing host toxicity. In this application, data will be presented validating the rationale for this "Trojan Horse" approach in which allogeneic hbMSCs are genetically-engineered to express a recombinant pro-aerolysin protein protoxin. While initially inactive, this protoxin is engineered to be selectively hydrolyzed to a picoMolar killing molecule by the enzymatic activity of a protease [i.e.. Prostate Specific Antigen (PSA)] which is only enzymatically active in high levels within the stroma at sites of prostate cancer. Since hbMSCs are being tested in clinical trials for regenerative medicine and recombinant PSA activated pro-aerolysin is in clinical testing as local therapy for prostate diseases, the proposed use of PSA-activated pro-aerolysin expressing hbMSCs could rapidly enter clinical development as systemic therapy for lethal metastatic prostate cancer based upon the successful completion of the following specific aims.
Prostate cancer is the most common, non- skin, malignancy of males in the USA. Despite treatment, over 25,000 males will die during the next year from this devastating disease due to the continuous growth of prostate cells which have spread throughout the patient's body. Recent studies have documented that a specific type of bone marrow derived cell, termed Mesenchymal Stem cell (MSC), leaves the bone marrow and relocates to sites throughout the body containing these disseminated prostate cancer cells because these cancer cells are releasing attractive factors for these MSCs. In this project, advantage will be made of this targeting of MSC to delivery killing agents selectively to these sites of prostate cancer sparing general host toxicity.
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