Treatment for localized prostate cancer is surgery or radiation therapy, usually accompanied by the use of drugs that starve the tumor of androgens, the male hormone that drives prostate tumor growth. Once prostate tumors become androgen-independent and have spread, there is only one treatment that provides improvement in survival, namely prednisone combined with taxotere, a chemotherapeutic agent. However, the improvement in survival is modest (3-4 months), and clearly more effective treatments for patients with androgen-independent tumors are needed.

Mounting evidence supports the concept that in prostate cancers, the growth of the tumor is generated by a few cells that give rise to the bulk of the tumor. These cells are termed tumor-initiating cells or cancer stem cells. Experiments thus far indicate that these cells are resistant to the commonly used chemotherapeutic agents and re-grow the tumor after treatment with known chemotherapeutics. Therefore, there are compelling reasons to find new agents to target these tumor-initiating cells.

We have focused on finding inhibitors of a protein essential for survival of these stem cells called Bmi-1. By working closely with a New Jersey Biotech company (PTC Therapeutics), we have identified three compounds that inhibit this stem cell growth factor at low concentrations, using human prostate cancer cell lines and patient cells. We now propose to test these three compounds using a large enough number of fresh samples obtained directly from prostate cancer patients, both in cell culture and using the zebrafish, as a novel, rapid, and inexpensive drug screen. The zebrafish are used as living incubators for human cells to allow for testing different doses and combinations of these compounds with other drugs against the growth of prostate cancers from a large number of patients. The zebrafish assays also can tell us how toxic these compounds are and allow us to focus on safer drugs. The initial studies in the zebrafish also allow us to utilize only a small amount of tissue from each patient, and therefore we will be able to test many different doses and combinations of treatment. Once an effective regimen is identified in the zebrafish incubators, these studies will be further confirmed using the more established mice tumors from human cells with our partnering Principal Investigators. The animal studies will provide the best possible treatment strategy for using these novel Bmi-1 inhibitors in human clinical trials.

Our goal is to identify one or more compounds that will be used in patients with androgen-insensitive tumors, alone and in combination with other agents. We expect that within the time frame of this grant (3 years), a compound(s) will be identified and a clinical trial initiated. The Gallo Prostate Cancer Center is within the Cancer Institute of New Jersey, which is the only National Cancer Institute-designated comprehensive cancer center in the state of New Jersey. The center treats all men from throughout the state of New Jersey including veterans, and also treats patients referred to the center from the affiliated Department of Veterans Affairs (VA) hospitals in New Jersey and New York. We expect that this new therapy would benefit a large number of prostate cancer patients, including those from the surrounding VA hospitals. The future trial is designed to include all eligible patients including veterans.