Protein That Suppresses Androgen Receptors Could Improve Prostate Cancer Diagnosis, Treatment

ScienceDaily (May 20, 2009) — A protein that helps regulate expression of androgen receptors could prove a new focal point for staging and treating testosterone-fueled prostate cancer, Medical College of Georgia researchers say.

Levels of the protein, βarrestin2, are lower in some prostate cancer cells than in normal prostate cells while expression of testosterone-fed androgen receptors is higher, they recently reported in Proceedings of the National Academy of Sciences Online Early Edition.

"An increase in the number of androgen receptors is believed responsible for prostate cancer progression in men with advanced disease," says the study's corresponding author, Dr. Yehia Daaka, Distinguished Chair in Oncologic Pathology in the MCG School of Medicine.

With increased numbers of androgen receptors, prostate cancer can make use of the limited testosterone available after a diseased prostate gland is removed or after testosterone production is blocked by drug therapy. In fact, the increased number of androgen receptors may mutate so they can start feeding off other steroids or even growth factors, Dr. Daaka says.

These wily skills help explain why cancer returns despite initially promising treatment results.

"It is clear that signaling by the androgen receptor is paramount for not only the initiation but also the progression of the disease, including escape to a hormone-refractory disease," he says. Moves androgen receptors make to support cancer growth make it "unbeatable at this point," for some patients.

However increased levels of βarrestin2 appear to halt the potentially deadly increase in androgen receptor expression, the MCG research team has found.

Androgen receptors have co-factors that can activate or repress their activity. "You could make the leap and say perhaps prostate cancer initiation and progression may be regulated by expression or non-expression of these co-factors," says Dr. Daaka, a Georgia Cancer Coalition Distinguished Cancer Scholar.

Their studies in human tissue – both in culture and transplanted into mice – show this appears the case for βarrestin2. First the team identified βarrestin2 as cofactor for androgen receptors. Next they found a reciprocal relationship: androgen receptor expression is low when βarrestin2 expression increases. That's the scenario in healthy prostate cells while the exact opposite is true in some prostate cancer. When they forced increased expression of βarrestin2, androgen receptor expression and activity went down.

βarrestin2 locks up an androgen receptor by binding to it, then the pair bind to yet another protein, ubiquitin ligase, which tags the receptor as waste and the trio make their way to the cell's garbage dump. "The neat thing about it is βarrestin2 inhibits or blunts the androgen receptor by promoting its degradation. So it disappears," Dr. Daaka says.

His future studies include determining what happens when βarrestin2 expression is further decreased in the face of prostate cancer. These studies will also help determine how big a player βarrestin2 is in prostate cancer progression, says Dr. Daaka, noting that numerous other corepressors and activators of androgen receptors are known.

Since all the happenings occur inside prostate cells, the findings don't point toward a new blood or urine test for prostate cancer but could lead to new ways to stage prostate cancer from the first biopsy. In fact, Dr. Daaka and his team already are collecting samples from patients whose cancer has been staged to see if specific levels of βarrestin2 expression correlate with different stages of disease.

Another goal is to develop a small molecule that can get inside a patient's cell and mimic βarrestin2's ability to suppress androgen receptor expression and so restore healthy levels found in prostate cells.

Prostate cancer falls behind skin cancer as the second most common cancer in men and more than 192,000 new cases will be diagnosed this year in the United States, according to the American Cancer Society.

Collaborators include Dr. Vijayabaskar Lakshmikanthan, postdoctoral fellow; Dr. Lin Zou, former postdoctoral fellow; Jae Kim, graduate student; Dr. Nidia C. Messias, assistant professor; and Dr. Zhongzhen Nie, assistant professor; from the MCG Department of Pathology; and Drs. Allison Michal and Jeffrey L. Benovic from Thomas Jefferson University.

Drug Shows Activity In Men With Advanced Prostate Cancer

ScienceDaily (Apr. 8, 2009) — A new multi-center study shows that an experimental drug lowers prostate specific antigen (PSA) levels – a marker for tumor growth – in men with advanced prostate cancer for whom traditional treatment options have failed. The study, led by researchers at Memorial Sloan-Kettering Cancer Center (MSKCC), is published in Science Express, the online version of the journal Science.

Most men with metastatic prostate cancer eventually build up resistance to the drugs that lower or block male hormones and develop a more aggressive form of the illness called castration-resistant prostate cancer (CRPC), or hormone-refractory disease. According to the study's findings, investigators studied two novel compounds, RD162 and MDV3100, and not only gained an understanding of their novel mechanism of action, but found that these agents showed activity in CRPC cells in culture and in mice.

The study also reports on a Phase 1/2 trial of MDV3100 in 30 patients with advanced CRPC and found that 22 out of 30 men showed declining PSA levels, and 13 out of 30 men (43 percent) had PSA levels fall by more than half.

Several years ago, the senior author of the study, Charles Sawyers, MD, and his colleagues at the University of California, Los Angeles (UCLA), uncovered a potential reason why metastatic prostate cancer patients eventually relapse with CRPC. This insight was used to discover RD162 and MDV3100.

"It's gratifying to know that our hypotheses about why men develop resistance to currently available treatments are confirmed and, most importantly, that there are already patients who are benefiting from our research," said Dr. Sawyers, Chair of the Human Oncology and Pathogenesis Program at MSKCC and a Howard Hughes Medical Institute investigator.

Current treatments for men who have advanced prostate cancers inhibit the activity of male hormones that help drive tumor growth. Many of these drugs disrupt the androgen (male hormone) receptor, which helps regulate cell proliferation, but tumors eventually become resistant to the drugs by expressing higher levels of the receptor. Preclinical studies by Dr. Sawyers and others have demonstrated that CRPC cells have increased expression of the androgen receptor and that overexpression of this receptor may contribute to the progression of disease.

Based on this information, Dr. Sawyers initiated a collaboration with Michael Jung, PhD, Professor of Chemistry at UCLA, that led to the discovery of a number of nonsteroidal, small molecule antiandrogen compounds, including MDV3100, which has been shown to retain its anticancer activity, even when the receptor's expression is elevated.

"The discovery and initial development of this drug was a collaborative effort all done in the academic setting, without reliance on the engine of the pharmaceutical industry that typically drives drug development," said Dr. Sawyers.

Dr. Jung's group synthesized the compounds, which Dr. Sawyers' team then evaluated using prostate cancer mouse models engineered to highly express the androgen receptor, mimic progression to castration-resistant disease, and reflect the biology of clinical drug resistance.

According to the new study, the team of researchers tested various compounds to block the androgen receptor in CRPC cells. They chose to further evaluate the drug RD162 and a closely related compound, MDV3100. According to their findings, both drugs inhibit the androgen receptor function by impairing the receptor's ability to enter a CRPC cell's nucleus (called nuclear translocation), blocking it from binding to the DNA of its target genes, and preventing the cell from growing.

They found that both compounds worked well in cells in culture, shrank tumors in mice, maintained tumor shrinkage for months, and prevented the androgen receptor from activating additional genes later in the process, or "downstream." Other currently approved drugs cannot disable the receptor in such a way.

The biopharmaceutical company Medivation, Inc., licensed RD162 and MDV3100 from UCLA in 2006 and has already completed enrollment in the first human trial of oral MDV3100 – a Phase 1/2 clinical trial, which was led by investigators at MSKCC and conducted through the Prostate Cancer Clinical Trials Consortium.

The Consortium is sponsored by the Department of Defense and the Prostate Cancer Foundation. The trial enrolled men with metastatic, castration-resistant prostate cancer who relapsed after treatment with conventional hormone therapy and demonstrated anti-prostate cancer effects beginning with the first patient treated with MDV3100 at the lowest dose. Further positive results from an additional 110 patients who received the drug at higher doses were recently reported at the ASCO Genitourinary Cancers Symposium in February 2009.

"The declines in PSA levels observed thus far and the general tolerability of this treatment are encouraging," said Howard Scher, MD, a study co-author and Chief of the Genitourinary Oncology Service at MSKCC. "I am looking forward to continuing the study of this drug, which has the potential to be a powerful tool in a limited arsenal of treatments against this deadly form of the disease." A Phase 3 trial is planned to begin later this year.

The study was supported in part by the Prostate Cancer Foundation, the National Cancer Institute, and a Prostate Cancer Research Program Clinical Consortium Award.

Prostate Cancer

Emerging Therapies

In labs around the world, researchers are busy identifying new drugs, new regimens, and new treatment approaches that might prove beneficial to men with prostate cancer. Most of these investigational agents are being tested in men with advanced prostate cancer: Therapy options for men at this stage of disease are often not effective enough to halt progression of the disease, and men are typically affected by side effects from the disease and/or the medications that they’re taking. It’s therefore the perfect stage at which to test out new drugs because any improvement will likely be rapidly noticed and much appreciated.


The Goal of Targeted Therapies

Chemotherapy drugs can play an important role in improving the lives of men with advanced prostate cancer, but they often don’t distinguish between tumor cells and healthy cells and can kill off some normal cells along the way. So-called targeted therapies, by contrast, are drugs that are specifically designed to interfere with the way cancer cells grow, with the way cancer cells interact with each other, and/or with the way that the immune system interact with the cancer.

There are a number of different kinds of targeted therapies being investigated for prostate cancer. As of yet, none have been approved by the FDA for use in prostate cancer, but the excitement generated by some of the early studies have led many researchers to believe that it’s only a matter of time before a targeted therapy is found that can result in better outcomes overall.


Interfering With Cancer Cell Growth

All cells in the body, including cancer cells, rely on a complex communication system to know when to grow, when to divide, and when to die. This system uses specialized proteins, fats, and other substances to tell the different cells or parts of cells how to act. Over the years, cancer researchers have been studying ways to interfere with the signaling system that regulates the growth of cancer cells.

So far, interfering with cellular signaling to halt cancer cell growth hasn’t yet proven to be a very effective strategy in prostate cancer. But in the process of learning which drugs might work and why, researchers found that the strategy of adding a "targeted therapy" to other effective drugs in order to see better results than with either drug alone is an important part of cancer research. The idea is to exploit the synergy between the two drugs, or the ways in which the two drugs might work together to fight off the cancer.


Interfering With Cancer Cell Spread

As cancer cells divide and start to spread, new blood vessels sprout from the old ones to help supply the necessary nutrients to the new tumor site via a process called angiogenesis. If angiogenesis could be inhibited, researchers theorized, the new tumor cells would die and the cancer’s growth would be halted.

In 2004, the angiogenesis inhibitor bevacizumab (Avastin) was approved by the FDA for use in colorectal cancer. Since then, it has been shown to improve outcomes in women with breast cancer, and is currently being studied in a number of other cancer types, including prostate cancer. Although no other drugs currently available were designed to specifically act as an angiogenesis inhibitor, researchers have found that the drug thalidomide (Thalomid) has some anti-angiogenic properties, and is also currently being tested in men with prostate cancer.


Harnessing the Immune System to Fight Off Cancer Cells

In order for the immune system to fight off foreign invaders, it has to learn to recognize what’s normal and what’s not normal. Unfortunately, because cancer cells start out as normal healthy cells, the immune system never has a chance to learn to distinguish between the normal cell and the cancer cell.

Unlike preventive vaccines, which are designed to teach the immune system to develop a way to fight off a specific virus should it come into contact with that same virus again, therapeutic vaccines stimulate the immune system to recognize and fight certain proteins specific to cancer cells. Each of the therapeutic vaccines currently being tested in men with advanced prostate cancer works in a slightly different fashion, but all are designed to harness the immune system’s ability to fight off disease and teach it to fight off prostate cancer cells.