Based upon substantial published literature from multiple groups, as well as unpublished studies to be presented from the applicants'laboratories, there is strong documentation that bone marrow-derived Mesenchymal Stem Cells are released into the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)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Teply, Benjamin A; Wang, Hao; Luber, Brandon et al. (2018) Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol 19:76-86
Zennami, Kenji; Choi, Su Mi; Liao, Ross et al. (2018) PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance. Mol Cancer Res :
Bhanvadia, Raj R; VanOpstall, Calvin; Brechka, Hannah et al. (2018) MEIS1 and MEIS2 Expression and Prostate Cancer Progression: A Role For HOXB13 Binding Partners in Metastatic Disease. Clin Cancer Res 24:3668-3680
Antonarakis, Emmanuel S; Lu, Changxue; Luber, Brandon et al. (2018) Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide. Eur Urol 74:218-225
Joshu, Corinne E; Peskoe, Sarah B; Heaphy, Christopher M et al. (2018) Current or recent smoking is associated with more variable telomere length in prostate stromal cells and prostate cancer cells. Prostate 78:233-238
Krueger, Timothy E G; Thorek, Daniel L J; Denmeade, Samuel R et al. (2018) Concise Review: Mesenchymal Stem Cell-Based Drug Delivery: The Good, the Bad, the Ugly, and the Promise. Stem Cells Transl Med 7:651-663
Shrestha, Eva; White, James R; Yu, Shu-Han et al. (2018) Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer. J Urol 199:161-171
Lu, Yunqi; Hu, Zhongyi; Mangala, Lingegowda S et al. (2018) MYC Targeted Long Noncoding RNA DANCR Promotes Cancer in Part by Reducing p21 Levels. Cancer Res 78:64-74
Das, Swadesh K; Pradhan, Anjan K; Bhoopathi, Praveen et al. (2018) The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion. Cancer Res 78:2852-2863
Karnes, R Jeffrey; Choeurng, Voleak; Ross, Ashley E et al. (2018) Validation of a Genomic Risk Classifier to Predict Prostate Cancer-specific Mortality in Men with Adverse Pathologic Features. Eur Urol 73:168-175

Showing the most recent 10 out of 750 publications