Sylvester Comprehensive Cancer Center

Sylvester Researcher Uncovers Potential Therapeutic Target for Prostate Cancer

02.13.2009

Clinical Trial Already Underway

A new discovery by the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine points the way to critically important treatment possibilities for patients with advanced prostate cancer in whom chemotherapy and hormone therapy have failed.

Patients with advanced prostate cancer who do not respond to hormone therapy, or in whom it stops working altogether, are commonly treated with docetaxel. However, that therapy commonly loses its effectiveness six to eight months into treatment, and in a significant number of patients, never works at all.

Rakesh Singal, M.D., associate professor of medicine and member of the Prostate, Bladder and Kidney Cancers Site Disease Group at Sylvester, led the study and is conducting the only clinical trial surrounding the discovery. Dr. Singal has been studying methylation-mediated transcriptional regulation in prostate and other cancers. In many cancers, malignant cells are able to proliferate by shutting down the body’s natural defenses, which include apoptosis or cell death and DNA repair. Repression of genes involved in ‘apoptotic’ or ‘cell death’ pathway may result from ’DNA methylation’. DNA methylation refers to a modification of DNA without a change to the original DNA sequence, resulting in alteration in gene expression.

Over the last several years, scientists have determined that DNA methylation and its impact on gene regulation can play a major role in targeted therapy. Cancer cells commonly show major disruptions in DNA methylation patterns. While scientists don’t yet fully know how cancer cells control methylation, the mechanism can be reversed. Dr. Singal closely examined the role of DNA methylation in cancer in an article published in the November 2004 issue of the Journal of Clinical Oncology.

For this current study, Dr. Singal worked with Kavitha Ramachandran, Ph.D., associate scientist at Sylvester, Isildinha M. Reis, Ph.D., research associate professor of biobehavioral oncology cancer control at Sylvester, and other laboratory associates, along with researchers from Heinrich Heine University in Dusseldorf, Germany. The scientists set out to investigate the methylation-mediated repression of a specific gene, GADD45α, knowing that it plays a role in DNA repair, cell cycle control and apoptosis or cell death. Researchers had already identified GADD45α as a key player in docetaxel chemotherapy mediated apoptosis or cell death.

Dr. Singal and his research team found that methylation-mediated repression of the growth arrest and DNA damage inducible α gene (GADD45α) in prostate cancer inhibits the effect of the docetaxel treatment. They then reversed the methylation of GADD45α, by treating prostate cancer cell lines with drugs that inhibit the ‘methylation’ process. What they discovered was a reactivation of GADD45α in these cells. Consequently, the cells exhibited renewed sensitivity to docetaxel chemotherapy, indicating that GADD45α is a potential target for the treatment of prostate cancer. The study results, which Dr. Singal describes as “extremely novel,” are published in the February 15 issue of Cancer Research, a journal of the American Association for Cancer Research.

Moreover, Dr. Singal sees this pathway as a gateway for much more. “This is going to be important not only for prostate cancer. It could be applicable for other cancer tumors.” Dr. Singal believes lung, breast and colon cancer patients may benefit from this discovery.

The results from the preclinical study were so promising that Dr. Singal was able to initiate a first of its kind clinical trial, using a drug that reverses the methylation process. The Sylvester Comprehensive Cancer Center is the only site for the Phase I/II study of azacitidine, docetaxel and prednisone for patients with metastatic hormone refractory prostate cancer who have progressed during or after treatment with docetaxel chemotherapy. Right now, a dozen patients are enrolled in this study and the results are “encouraging.”

To find out more or enroll in Dr. Singal’s clinical trial, call 305-243-9544 or 1-866-574-5124 between the hours of 8:30 a.m. and 5:00 p.m., Eastern Standard Time (except holidays).

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