The Molecular Bomb Squad

Prostate cancer research at the Center of Excellence on Urologic Disease

Picture a time bomb encased in a black box. Hundreds of small switches on the outside of the box are connected to wires on the inside. The wires, in turn, connect to the bomb’s detonator. Flip one group of switches, and the bomb explodes. Flip another set, and you’ll slow the clock’s countdown. Just as in the movies, you aren’t given any clues. Where would you begin in defusing the bomb?

This is the conundrum faced by prostate cancer researchers. When the time bomb of cancer explodes, we know that specific have been flipped, but there’s no way to peer directly into the black box to determine which sets of wires and switches have been activated.

In the world of cancer, the ‘wires’ are molecular pathways that control the cell’s day-to-day operation. The ‘switches’ are receptors that allow the cell to communicate with its surroundings. When a receptor is triggered by an element in its environment (such as a hormone that flows through the bloodstream), it sends a signal over the molecular pathways to the cell’s genetic machinery, causing the cell to grow, divide or die. In normal cells, these receptors and pathways operate like finely tuned machines. But in cancer, cells behave as if switches were flipped indiscriminately on the surface of the black box. This ‘signaling gone haywire’ is one reason why cancer cells grow out of control.

Cancer researchers must find creative ways to indirectly examine the wires and switches in cancer cells. Two of those scientists at NYU School of Medicine are Dr. Michael Garabedian, Associate Professor of Microbiology and Urology, and Dr. Susan Logan, Assistant Professor of Urology and Pharmacology. Garabedian and Logan lead the Androgen Receptor Working Group at the Center of Excellence on Urologic Disease at NYU Langone Medical Center.

Garabedian has studied hormone receptors for many years. When Dr. Samir Taneja joined the Department of Urology in 1996, the two developed an interest in the androgen receptor, which is of critical importance in prostate cancer. In healthy men, the androgen receptor responds to the male sex hormone testosterone, resulting in the development of male physical characteristics. But in prostate cancer, the androgen receptor signaling mechanism is disrupted.

By experimentally cutting different wires or flipping different switches—in other words, methodically shutting down or activating molecular pathways and receptors—the group discovered a molecule they dubbed ART-27.

In collaboration with Logan, the researchers found that ART-27 was present in mature prostate cells but absent from immature cells. Since cancer cells are typically immature (‘undifferentiated’, in scientific parlance), the researchers hypothesized that boosting the level of ART-27 might make the deadly cells mature and stop multiplying. Logan’s subsequent experiments have confirmed this expectation—increasing the amount of ART-27 does, in fact, slow the growth of human prostate cancer cells cultured in the laboratory. The group is currently working on replicating these results in a mouse model of prostate cancer.

In more recent research, Garabedian, Logan and co-workers found that ART-27 is present at lower amounts in prostate cancer cells than in normal prostate cells. Moreover, by examining tissue samples from men with prostate cancer, the group found that the men with higher levels of ART-27 in their prostates experienced better medical outcomes. They theorized that if they could boost the level of ART-27, they might be able to slow or reverse the course of the disease.

Garabedian, Logan and their colleagues at the Center of Excellence continue to explore the maze of pathways that connect ART-27 to prostate cancer. In one project, the group aims to increase the expression of ART-27 through new drugs or dietary supplements. In another line of research, they are exploring the role of ART-27 in androgen-independent prostate cancer—a hard-to-treat, late stage of the disease that develops after men have been treated with hormone deprivation therapy.

Through the continued support of the Center of Excellence on Urologic Disease, the group hopes in the near future to find the key to permanently defusing the prostate cancer time bomb.