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From mice to men

Norman Greenberg's translational-research studies in mice aim to find clues to the causes of prostate cancer and to develop new therapies
Dr. Norman Greenberg
Dr. Norman Greenberg looks at a tissue section from a cancerous mouse prostate gland. His research focuses on identifying the cellular pathways that control how normal prostate cells give rise to cancer, which could lead to new treatments for the disease. Photo by Todd McNaught

Dr. Norman Greenberg, a prostate-cancer researcher, says that studying the disease is often like finding a wrecked car without having witnessed the accident.

"If you're not there to watch the crash, you don't know what happened," said Greenberg, who moved his laboratory from Baylor College of Medicine in Houston to the Clinical Research Division in January. "It's hard to work your way back to what caused it. We want to start at the beginning."

Thanks to a model system he developed several years ago to study how prostate tumors arise from healthy cells, Greenberg — and hundreds of his colleagues around the world — have a powerful tool to allow them to compose a detailed accident report of the disease process.

Rather than studying cancer cells plucked from a tumor and grown in a laboratory dish, Greenberg wants to watch healthy cells from the time they begin to skid out of control until their brakes on normal growth fail completely. To do so, he developed a strain of mice called TRAMP — for Transgenic Adenocarcinoma of the Mouse Prostate — that are highly susceptible to developing prostate cancer.

TRAMP mice have begun to reveal much about the genes, proteins and environmental factors that cause prostate cancer. The mice also have been a reliable proving ground in which to test whether specific drugs or dietary factors might be successful treatment or prevention strategies for the disease before they are tested with patients. Several of these drugs have shown promise in human clinical trials.

As the center expands its efforts to understand and cure solid cancers, Greenberg's research will serve as a bridge between the lab bench and the patient's bedside. Such translational research, as it is known, aims to conduct the proof-of-principle studies required to adapt basic discoveries into medical practice.

"There has been a paucity of good animal models for human cancers," said Dr. Fred Appelbaum, Clinical Research Division director. "Norm has developed a mouse model that reliably mimics human disease. The mice enable him not only to ask basic questions about disease pathogenesis, but also provide a system in which to design and evaluate new treatments and diagnostics."

A native of Canada, Greenberg obtained an undergraduate degree in microbiology and parasitology from the University of Toronto. He completed a Ph.D. in microbiology and molecular biology at the University of British Columbia, where he studied gene regulation in bacteria. Before joining the faculty at Baylor in 1991, he conducted postdoctoral research there with Dr. Jeffrey Rosen. During that time, he became an expert in creating genetically engineered, or transgenic, mice, a talent that paved the way for the invention of the TRAMP mouse.

Some scientists question whether mice can serve as useful models for human disease, since despite many shared characteristics the two species are, after all, very different. But Greenberg says that prostate cancer in TRAMP mice, which are genetically engineered to develop spontaneous prostate tumors, is remarkably similar to the condition in men. His lab came up with a list of 11 features that an ideal prostate-cancer animal model would possess — and TRAMP has them all.

"Like the human form of the cancer, the mouse tumors arise from the same type of prostate tissue," Greenberg said. "The mice also first display a precancerous condition called PIN, the tumors shrink when deprived of hormones and — a unique feat for such models — they even metastasize to the bone, which is where the cancer can spread in men."

From the start, Greenberg insisted that his mouse models would have to closely mimic human prostate cancer because his ultimate goal is to find a way to cure or prevent the disease. With more than a quarter of a million men expected to be diagnosed with prostate cancer in the United States this year — and nearly 30,000 expected to die from it — he describes the illness as "a scourge upon the land."

"We know a lot about prostate cancer, but cure rates for the disease once it has spread beyond the prostate aren't nearly where we want them to be," he said.

Androgen-receptor protein

Almost all men with early-stage cancer, which is confined to the prostate, can be cured with surgery. Once the disease has spread, survival rates drop dramatically. Many prostate cancers are now caught at an early stage using the PSA blood test, although experts believe that the test detects tumors that would never cause harm and prompts many men to undertake unnecessary treatment.

Patients whose disease is more advanced often receive therapy to deprive the tumor of hormones that may spur it to grow. Men produce a variety of hormones collectively known as androgens, which include testosterone and some of its derivatives. The hormones are required for normal development of the prostate during puberty. Since the 1940s, beginning with research conducted by Dr. Charles Huggins, it has been known that castration — removal of the testicles, which produce the androgens — causes prostate tumors to shrink. Since then, certain drugs and forms of radiation therapy have been developed that mimic castration. None, Greenberg says, can cure the disease.

"Over the years, every combination of androgen-deprivation therapy has been tried — surgical and chemical — but none are very curative," he said. "There's a very dramatic initial response where the tumors shrink, but only about 20 percent of men who get hormone therapy survive five years. Androgen is not the Achilles heel we thought it to be."

Greenberg now believes that insight into the disease requires focusing on the receiving end of the androgen hormone signal, a protein known as the androgen receptor that is found within prostate epithelial cells. When androgen binds to the receptor, the receptor travels to the cell nucleus and triggers a domino effect that results in both profound and subtle alterations to the cells' growth program. Since it is now known that many men with prostate cancer may have acquired mutations in their androgen receptors even before they begin hormone therapy, the protein may hold important clues to how the disease develops, progresses and becomes resistant to hormone deprivation.

With a response to hormone therapy similar to that seen in men, the TRAMP mice provide an ideal system to explore the workings of the androgen receptor.

"If we take TRAMP mice with early prostate cancer and deprive the mice of androgen, 80 percent will fail and many will get even bigger and more advanced tumors," Greenberg said. "They also get more metastases. This may be true for patients as well, so it's critical that we start to understand what's going on."

Mutations in mice

He and collaborators have identified mutant versions of the androgen receptor that arise in mice whose tumors become resistant to androgen therapy. Interestingly, they have found that the nature of the mutation varies depending on the type of therapy. More recently, the researchers also have begun to investigate analogous mutations in human prostate cancer, which could help explain why cancers lose their ability to respond to hormone therapy and ultimately may lead to the creation of more effective therapies. Promising treatments will undergo testing in TRAMP mice.

"It may be that the androgen receptor pathway, when it's intact, actually inhibits growth," he said. "This goes against the established dogma."

Instead, he hypothesizes that certain alterations in the androgen signaling pathway — including but not limited to spontaneous mutations in the androgen receptor — may force the cell into a state of uncontrolled growth, regardless of whether or not the hormone is present.

Hormones are not the only factors that control development of the prostate. Greenberg's lab is also using the TRAMP mice as well as an exhaustive list of other new models to investigate the role of non-hormonal growth factors, in particular members of a family of proteins known as the fibroblast growth factors, in prostate cancer.

From lab to patient care

To watch how prostate tumors develop and respond to treatment, Greenberg uses imaging technologies such as MRI (magnetic resonance imaging), CT (computerized tomography) and PET (positron emission tomography) scanning. The center recently purchased a CT machine for imaging tumors in small animals and plans to acquire an MRI, and the University of Washington houses one of the country's leading departments for imaging technology.

The real goal, Greenberg said, is to move the discoveries made in the laboratory into the Seattle Cancer Care Alliance, where they may offer new hope to patients with prostate cancer. He is optimistic that the pipeline to achieve this exists among researchers at Fred Hutchinson and local collaborators.

"We take our cues from epidemiologists who study the causes of prostate cancer and collaborate with clinicians who are working with patients," he said. "Our lab's strength is in preclinical studies — figuring out whether potential treatments work in the genetically engineered animals. With these mouse models, we're setting the bar higher so that we can more rapidly identify, select and develop therapies with the highest likelihood of success in man.

"Ultimately, we're after cures," he said.

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