Targeting Drugs for Cell Division Pathway in Prostate Tumors Paves Way for Clinical Trials
New Brunswick, N.J.– 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.
The author team also includes Nitu Bansal, PhD; Neil Campbell, MSc; Daniel Medina, PhD; Robert DiPaola, MD; and Joseph R. Bertino, MD, all of CINJ.
The work represented by CINJ members is among the 6,300 abstracts being presented at the gathering, which is featuring more than 17,000 researchers, healthcare professionals, and patient advocates. The event is open to registered participants.
About The Cancer Institute of New Jersey
The Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center dedicated to improving the detection, treatment and care of patients with cancer, and serving as an education resource for cancer prevention. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support CINJ, call 732-235-8614 or visit www.cinjfoundation.org. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.
The CINJ Network is comprised of hospitals throughout the state and provides a mechanism to rapidly disseminate important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Memorial Hospital, Carol G. Simon Cancer Center at Overlook Hospital, Cooper University Hospital and Jersey Shore University Medical Center. Affiliate Hospitals: Bayshore Community Hospital, CentraState Healthcare System, JFK Medical Center, Mountainside Hospital, Raritan Bay Medical Center, Robert Wood Johnson University Hospital at Hamilton (CINJ at Hamilton), Saint Peter’s University Hospital, Somerset Medical Center, Southern Ocean County Hospital, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate