CINJ researches identify new drug candidates that inhibits prostate cancer growth

Trying to break down a barrier that prevents effective treatment of prostate cancer, researchers from The Cancer Institute of New Jersey (CINJ) have identified candidate drugs that block a key protein responsible for tumor growth. Their work is being presented this week in Washington, D.C., during the 101st Annual Meeting of the American Association for Cancer Research (AACR). CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

Treatment for localized prostate cancer often consists of 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 approved treatment available for use, namely the anti-inflammatory drug prednisone combined with docetaxel, a chemotherapeutic agent. However, the improvement in survival after this treatment is modest (three to four months), and researchers have been exploring more effective treatments for patients with androgen independent tumors.

Mounting evidence supports the concept that in prostate cancer, tumor growth is generated by a small number of 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 chemotherapy, and therefore specific drugs that target these resistant cells would have therapeutic benefit.

A team approach led to the identification of subfractions of prostate tumor cells that are able to initiate tumors in zebrafish and other experimental models. The work involved collaboration among the CINJ laboratories of Drs. Joseph R. Bertino, Robert S. DiPaola, Daniel Medina and Hatem Sabaawy; and Dr. Thomas Davis (PTC Therapeutics, Piscataway, NJ), who provided the novel small molecule Bmi-1 inhibitors. Targeting the pathway that allows these tumor cells to continuously divide by genetic or pharmacological small molecule inhibition of the critical stem cell protein Bmi-1 resulted in antitumor effects.

The team demonstrated that tumor initiating cells from prostate cancers obtained directly from patients following surgery are sensitive to Bmi-1 inhibition. Through the development of a novel zebrafish xenograft, in which human prostate cells were allowed to grow and divide inside zebrafish, investigators were able to identify candidate Bmi-1 inhibitory drugs that target tumor-initiating pathways. By utilizing the transparent zebrafish model, scientists were able to see directly as prostate tumors grew, and how the agents worked to block their growth, in a live genetic environment that closely resembles that of a human.

Hatem Sabaawy, MD, PhD, a medical oncologist at CINJ and assistant professor of medicine at UMDNJ-Robert Wood Johnson Medical School, is the senior investigator. "These studies will likely provide the rationale for clinical trials utilizing novel drugs targeting resistant tumor stem cells for combination therapies in advanced prostate cancer. Moreover, in preclinical study as we advance toward the clinical trial stage, the continued use of zebrafish in this fashion will allow investigators to rapidly generate the necessary data pertaining to how tissue responds to select agents," he said. The work is funded by grants from the National Cancer Institute, the Department of Defense, and the New Jersey Commission on Cancer Research.