Resetting the Clock on Prostate Cancer

"Bench-to-bedside" research on the androgen receptor at NYU Langone

Testosterone is responsible for all things male: muscle mass, sex drive, broad shoulders, deep voice, and chest hair. But in men with advanced prostate cancer, this male sex hormone also helps feed cancer cells. That’s why the traditional treatment for men with this disease has been hormone deprivation—shutting down the body’s production of testosterone.

Unfortunately, while hormone deprivation can be successful in slowing cancer growth, it can have drastic side effects. Loss of sexual function and libido, decreased muscle mass, weight gain, low energy, increased risk of diabetes and heart attack, and changes in sleep pattern, mood, and cognitive function are all too common in men undergoing this therapy. To make matters worse, prostate cancer cells typically mutate over time and become resistant to hormone deprivation. This limited window of effectiveness and negative impact on quality of life has left doctors looking for other avenues to treat so-called “hormone-refractory” prostate cancer.

Motivated by these limitations, NYU Langone Medical Center researchers are looking for alternative methods to stop the growth of prostate tumors. One of those scientists is Dr. Anna Ferrari, an oncologist in the Department of Medicine and a member of the NYU Cancer Institute and the Center of Excellence on Urologic Disease, who maintains an active research laboratory in addition to her clinical practice. At NYU Langone, she has had the opportunity to translate her laboratory work on prostate cancer into new therapies that are tested in the clinic.

Early research

Dr. Ferrari has been studying prostate cancer since her early days as a clinician in the 1980s. At that time, most men with prostate cancer arrived at her clinic with advanced disease, with few treatment options besides castration and chemotherapy. “It was awful,” says Ferrari, “and it got me thinking about other ways that we could attack this cancer.”

In the early 1990s, Dr. Ferrari and other prostate cancer researchers began to focus their attention on one molecule: the androgen receptor. In healthy men, the androgen receptor is found throughout the body and acts like a “radio receiver” attuned to testosterone. When it comes in contact with male sex hormones that flow through the bloodstream, it “rebroadcasts” a signal to the cell’s genetic machinery, causing the development of male physical characteristics. But in prostate cancer, malignant cells rebroadcast an abnormally strong signal, even when levels of testosterone are very low. This led researchers to theorize that abnormal activation of the androgen receptor was responsible for the progression of prostate cancer. The question was, how?

Ferrari collaborators and lab members at the NYU Cancer Institute (left to right: Xiao-Mei Liu, M.D.; Anna C. Ferrari, M.D.; Xiaojun Liu, M.D.; Alejandro Gomez-Pinillos, M.D.

Dr. Ferrari began to explore this question using a set of prostate cancer cells she had cultivated in the laboratory. The growth of these cells was still halted by hormone deprivation, just as in men with early-stage disease. But by treating the cells just as she would treat a patient with prostate cancer—depriving them of testosterone—she created a new set of cancer cells resistant to hormone deprivation, mimicking the “hormone-refractory” cancer found in men with advanced disease.

Dr. Ferrari and her research colleagues then uncovered a key piece of information: the androgen receptor (the testosterone “radio receiver”) was much more abundant in the new group of hormone-refractory cells than in their parent cells (which were still sensitive to hormone deprivation therapy). Armed with this knowledge, Dr. Ferrari and her colleagues began to explore ways to turn off the androgen receptor. If they could shut down its machinery, they posited, they might be able to reverse prostate cancer’s progression—or even find a way to destroy malignant cells without resorting to hormone deprivation.

Years of painstaking work culminated in an article published in the journal Cancer Research in 2008. In this paper, Ferrari and co-workers described a molecule, Purα, that normally limits the number of androgen receptors in cancer cells—but that was lacking in the hormone-refractory cells. When the scientists artificially restored Purα, the number of androgen receptors decreased—and the rogue cancer cells turned back into the tamer variety that was arrested by hormone deprivation therapy. “We were able to ‘turn back the clock’ in these cancer cells,” remarks Ferrari. The next step would be to replicate this phenomenon in humans.

From the laboratory to the clinic

Ferrari and other researchers will put the results of their laboratory work to the test in two upcoming clinical trials.

In the first study, which is awaiting final approval by the US Food and Drug Administration, the researchers will test Panobinostat, a drug that restores the suppressor Purα and prunes the overgrown androgen receptors found in hormone-refractory prostate cancer cells. Patients enrolled in the trial will take Panobinostat in combination with a second drug, Casodex, which prevents the androgen receptor from “rebroadcasting” its signal to cancer cells’ genetic machinery. This trial aims to reverse the course of prostate cancer and make hormone deprivation therapy effective once again.

In a second trial, now under review at the National Cancer Institute, Ferrari and colleagues will test two drugs in combination: one that prevents the androgen receptor from receiving testosterone’s signal, and another that stops it from activating the cancer cells’ genetic machinery. This trial could mark the beginning of a new treatment model: halting prostate cancer progression without hormone deprivation and its side effects. Ferrari also expects that using a combination of drugs may have a synergistic effect, not only slowing growth of new cancer cells, but also killing existing cancer cells.

Ferrari hopes that these trials will be just the beginning in a series of studies that test combination therapies and alternative means of treating prostate cancer. “Androgen receptor research is very promising in the near term,” says Ferrari. The coming years will tell if this translational research will truly reset the clock on prostate cancer.

Last updated March 24, 2009 by Dorothy Moore