Researchers from The Cancer Institute of New Jersey (CINJ) have identified candidate drugs that block a key protein responsible for tumor growth. Their research was presented at the recent Annual Meeting of the American Association for Cancer Research (AACR) which I had the good fortune to attend.
As we know the common treatment for localized prostate cancer consists of surgery or radiation, sometimes accompanied by the use of hormone therapy (ADT) that starves the cancer of androgens, the male hormone that drives prostate tumor growth. Eventually, some prostate tumors become androgen independent and will spread into other parts of the body (metastasize). Once this happens there is only one approved treatment available for use, chemotherapy with the anti-inflammatory drug prednisone combined with docetaxel.
According to the phase III studies of docetaxel (the chemotherapy agent), the expected extension in survival from derived from chemotherapy is a mere three to four months. Clearly, we are in desperate need of additional and improved treatments for late stage prostate cancer.
There is mounting evidence that in prostate cancer, as with other cancers, tumor growth and metastases are started by only a small number of cells called tumor initiating cells or cancer stem cells. Current experiments show that these cells are resistant to current chemotherapy, so new specific drugs that target these resistant cells are needed.
Drs. Joseph R. Bertino, Robert S. DiPaola, Daniel Medina and Hatem Sabaawy (;CINJ ) and Dr. Thomas Davis (PTC Therapeutics, Piscataway, NJ), identified subfractions of prostate tumor cells, novel small molecule Bmi-1 inhibitors that are able to initiate tumors in zebrafish and in other experimental models.
They found that 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 an anti-tumor effect.
They also 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.
Cancer Institute of New Jersey
Joel T Nowak, MA, MSW