Based upon substantial published literature from multiple groups, as well as unpublished studies to be presented from the applicants'laboratories, there is strong documentation that bone marrow-derived Mesenchymal Stem Cells are released into the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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-RPRB-7 (M1))
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Johns Hopkins University
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Guedes, Liana B; Morais, Carlos L; Almutairi, Fawaz et al. (2016) Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer. Clin Cancer Res 22:4651-63
Haffner, Michael C; Weier, Christopher; Xu, Meng Meng et al. (2016) Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. J Pathol 238:31-41
Barakat, David J; Mendonca, Janet; Barberi, Theresa et al. (2016) C/EBPβ regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome-lysosome fusion. Cancer Lett 375:152-61
Murtola, Teemu J; Gurel, Bora; Umbehr, Martin et al. (2016) Inflammation in Benign Prostate Tissue and Prostate Cancer in the Finasteride Arm of the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 25:463-9
Jackson, Christopher M; Kochel, Christina M; Nirschl, Christopher J et al. (2016) Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination. Clin Cancer Res 22:1161-72
Hedayati, Mohammad; Haffner, Michael C; Coulter, Jonathan B et al. (2016) Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation. Clin Cancer Res 22:3310-9
Trock, Bruce J; Fedor, Helen; Gurel, Bora et al. (2016) PTEN loss and chromosome 8 alterations in Gleason grade 3 prostate cancer cores predicts the presence of un-sampled grade 4 tumor: implications for active surveillance. Mod Pathol 29:764-71
Wu, Jianguo; Ivanov, Andrei I; Fisher, Paul B et al. (2016) Polo-like kinase 1 induces epithelial-to-mesenchymal transition and promotes epithelial cell motility by activating CRAF/ERK signaling. Elife 5:
Levy, Oren; Brennen, W Nathaniel; Han, Edward et al. (2016) A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer. Biomaterials 91:140-50
Lotan, Tamara L; Wei, Wei; Morais, Carlos L et al. (2016) PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer. Eur Urol Focus 2:180-188

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