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Duke Researchers Tackle Prostate Cancer

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Duke Health News 919-660-1306

Prostate cancer is the second leading cancer killer in men, claiming the lives of black men twice as often as white men. The problem is especially apparent in North Carolina where the African-American population has the nation's highest mortality rate from the disease.

It is a formidable opponent and scientists at Duke Comprehensive Cancer Center have stepped up their efforts to find ways to better treat and even prevent the disease. The division of urology, the department of surgery and other departments are building a Prostate Cancer Research Program, taking a multi-disciplinary approach to the problems of diagnosing, treating and preventing prostate cancer. Duke's team of researchers includes surgeons, cell biologists, epidemiologists, pathologists, radiation oncologists, medical oncologists.

The U.S. government's National Cancer Institute is a leading supporter of academic research into prostate cancer; other federal agencies including the Veterans Administration provide grant money as well. At Duke, federal money is supplemented by private donations, agreements with corporations and support from such organizations as the Jimmy V Foundation and the Association for the Cure of Cancer of the Prostate (CaPCURE).

Duke's prostate cancer research effort is now seeking major funding from the Department of Defense. If the grant application is approved, an additional $2.5 million will be dedicated to basic prostate cancer research at Duke, raising the total to about $4 million in federal funds.

The university is attacking prostate cancer on many levels, from studying the role of nutrition in prostate diseases to developing vaccines. The efforts are aided by a strong clinical program, which can provide tumor samples for basic research and access to patients for clinical studies.

Here are some highlights of Duke's ongoing prostate cancer research:

Impact of Nutrition

Granola versus bacon and eggs? A salad instead of a burger? For years some people have been watching what they eat to try to prevent heart disease, but can dietary change prevent cancer? Researchers at Duke are looking for answers.

Wendy Demark-Wahnefried, associate research professor of urology in the department of surgery, and Xu Lin, post-doctoral research assistant, are evaluating the effect of flaxseed. Flaxseed, which can be ground into flour or meal or pressed to obtain an oil, contains omega-3 fatty acids as well as dietary fiber - two substances that might be linked to cancer prevention.

In a sample of men with suspicious biopsies but no cancer, a low-fat diet and flaxseed supplementation appeared to improve the appearance of prostate cells from subsequent biopsies, says Demark-Wahnefried, leader of the pilot study. And in two men, blood levels of prostate specific antigen (PSA), which is routinely used to screen for possible prostate cancer cases, dropped to normal levels.

Now Duke researchers are looking at the effects of limiting fat intake versus taking flaxseed supplements. Volunteers diagnosed with prostate cancer who meet certain eligibility requirements are being accepted for this study.

Meanwhile, Xu Lin is examining the details of flaxseed's effects in mice. "In humans it is harder to measure biologic changes that occur because of diet because our lifespan is too long," she says. Fortunately, there are transgenic mice that serve as a good model of human prostate cancer. "We'll really be able to see what's happening throughout the mouse's growth, development of the primary cancer, and eventual development of metastases."

Patient studies are funded by the Committee for Urologic Research, Education, and Development at Duke, while the mouse studies are funded by a grant from the National Institute on Aging and by a private donation by the initial patient treated with flaxseed.

Effect of Race

In a large study, a team of Duke researchers is investigating the reasons behind mortality differences between black men and white men with prostate cancer. Black men not only are more likely to develop prostate cancer, but they also are more than twice as likely to die from it than white men.

"While African-American men typically have a later stage of disease at diagnosis, underlying reasons for mortality differences aren't clear," says Wendy Demark-Wahnefried, a research team member.

North Carolina has the highest mortality rate for black men diagnosed with prostate cancer, as well as the fourth largest population of African-American men in the country, making it a good place to examine race differences in this disease.

Among possible explanations for the mortality differences are treatments offered or chosen, different access to or beliefs about medical care and cancer screening, different occupation-related risk factors, different gene-environment interactions and different diets. So far, Duke research suggests that differences in treatment after diagnosis is not a contributing factor. Blacks and whites are offered the same services and make the same choices about their treatment, says Demark-Wahnefried. As a result, she said, differences related to early detection, environmental influences or genetic factors might provide explanations for mortality differences. Since farmers are twice as likely to get prostate cancer as the general population, the study is examining the possible effect of pesticide exposure as an explanation for mortality differences.

The team also has observed a connection between early onset baldness and risk of prostate cancer. The studies examining race and screening behaviors also are collecting data to clarify this apparent link.

These studies are funded by the National Cancer Institute and the Department of Veterans Affairs. An additional study is looking into preventing secondary medical problems that arise after cancer patients have finished treatment. It is being funded by the National Institute on Aging.

Vaccines for Prostate Cancer

Vaccines are designed to alert the immune system to recognize and fight off a foreign invader that would otherwise go undetected. Typically, vaccines are used to prevent even the initial episode of a disease. In cancer, however, the current goal is to teach the immune system to be an active ally against invading cancer cells once disease is present.

Disease-fighting white blood cells usually don't recognize cancer cells. Although the reason for this isn't understood, the effect is known - the body doesn't help save itself from the onslaught of tumor growth. Instead, outside agents like radiation and chemotherapy drugs are used to kill cancer cells. But researchers at the Center for Genetic and Cellular Therapies in the Duke Comprehensive Cancer Center have developed a way to uncloak tumor cells by teaching the immune system to recognize these cells as invaders.

First, potent immune-stimulating cells, called dendritic cells, are taken from the patient and expanded to provide enough for treatment. Next, researchers "make the cells smart" by introducing protein or genetic material from the patient's own tumor cells. Each dendritic cell takes the tumor's information and displays the tumor's proteins on its surface. When returned to the patient, the tattle-tale dendritic cells show the characteristic proteins to immune cells, which then hunt for and kill cancer cells with the proteins. These techniques are now being applied in early clinical trials in prostate cancer.

In a phase I study of men with advanced prostate cancer, Dr. Johannes Vieweg, assistant professor of urology in the department of surgery, is checking for an immune response caused by dendritic cells taught to express prostate specific antigen (PSA), which is a common protein on prostate cancer cells.

Because the patients' disease is advanced, researchers do not expect a clinical response, such as tumor shrinking or another indicator that the immune system is killing cancer cells. Instead, in this early trial, scientists are looking for clues that the immune system has been turned on. To do this, Duke researchers will be monitoring levels of white blood cells - specifically T-cells enlisted to attack cells with displayed tumor proteins. In addition, they will look at PSA levels in the blood and at a few other items as markers that the dendritic cells have relayed their message. If this initial trial looks promising, subsequent studies in men with less advanced disease will be needed before any therapeutic response can be detected, Vieweg says.

If the technique works, the vaccine could help prevent recurrence after prostate surgery. "With prostate cancer, if you can delay the disease a few years, you will have gained a lot," Vieweg says.

These clinical trials are funded by the National Institutes of Health, private contributions from patients interested in promoting vaccine research, and the Cancer Research Institute, a New York based not-for-profit organization dedicated to supporting both basic and clinical cancer immunotherapy research.

Use of Angiogenesis

Tumors need to create their own blood supply system to grow much larger than a pinhead, according to Dr. Sal Pizzo, professor and chair of pathology. Blocking the creation of new blood vessels -- a process called angiogenesis -- presents a relatively new target for cancer therapies.

In Pizzo's lab, research associate Tammy Moser has characterized how a protein called angiostatin binds to a receptor on the surface of the cells that line blood vessels. The receptor is called ATP synthase and is known to be the powerhouse inside cells. Their surprising result -- that ATP synthase is also outside cells and that it binds angiostatin -- has created a new flurry of research.

When angiostatin binds to ATP synthase, it blocks the energy-producing capability of the receptor, shutting down a growth mechanism for new blood vessels. However, angiostatin is a very complex molecule, making it difficult to synthesize the protein in large amounts and have it function properly. So researchers are looking at other pathways for potential therapies.

With a number of collaborators, Pizzo is searching for antibodies to the receptor's four distinct parts. One of the antibodies might act like angiostatin and thereby block energy production, stopping blood vessel growth.

The researchers also are searching through large numbers of peptides - very small proteins that are easier to make and control than large, complex proteins like angiostatin - for ones that behave like angiostatin. The scientists also are considering molecules that aren't at all like proteins. Sometimes these so-called "small molecules" can have the same effect on biological processes as proteins. Scientists say it's possible that one of these antibodies, peptides or small molecules might make a good drug for treating cancer by blocking tumors' blood vessel growth.

Mark Dewhirst, professor of radiation oncology and assistant professor of pathology, has developed a way to accurately measure the effects of these potential drugs on angiogenesis. Researchers in Pizzo's group will take advantage of the expertise available at Duke to evaluate potential new cancer treatments.

Pizzo's studies were funded by corporate agreements with Glaxo-Wellcome. The pending grant from the Department of Defense will provide the most funds for these prostate cancer projects.

Changing Character

Prostate cancer is sometimes an easy adversary to take on and sometimes it's an impossible opponent. Physicians say they know that a tumor that responds nicely to hormone therapy one day probably won't at some time in the future. But while researchers have known that prostate cancer becomes hormone independent, no one really knows how. They do know it's a bad thing when it happens. Hormone-independent prostate cancer is more aggressive and difficult to treat.

Dr. Mariano Garcia-Blanco is looking into a basic science question that may help explain how prostate cancer changes its character. He is studying a fairly new realization about RNA and proteins. For years, researchers thought each gene held instructions for only one related RNA molecule and that it in turn held directions for only one possible protein. But in fact, that's not the case: different cells can read the RNA differently.

"The bottom line is that from the same gene, you get two different messenger RNAs, and those two messenger RNAs will make two different proteins," Garcia-Blanco says.

The reason is a process called alternative RNA splicing, but scientists don't know exactly how it works. They do know that RNA is made of "exons," regions of RNA that can be translated into a protein, and "introns," which are areas that can't be deciphered between the parts that can be read. It turns out that different cells will read different exons from the same RNA, producing different messenger RNA, and ultimately different proteins.

Garcia-Blanco likens alternative RNA splicing to editing a film. You start with one long piece of film (the RNA), but by editing it differently, you can ultimately end up with two completely different movies (proteins).

He uses a prostate cancer model in rats to study alternative splicing and its connection to a tumor's switch to hormone independence. The tumor cells in his rats have a receptor called FGF-R2 that is related to cell growth. The receptor is created from the messenger RNA from a single gene. When cancer is hormone dependent and slower growing, the receptor form is called IIIb. But when cancer becomes aggressive and hormone independent, the receptor is slightly different and is called IIIc. Garcia-Blanco describes the change to IIIc as "receptor switching."

His prostate cancer model makes alternative splicing easy to study, he says, because each cell produces only IIIb or only IIIc, never a combination, and there isn't a third option. "We looked for the best model system to do this basic science," he says. Now his lab is trying to find out what other genes, proteins or processes regulate the switch from IIIb to IIIc.

"We don't know if this switch causes or is caused by the change to a more aggressive cancer, or if it's merely correlated somehow," Garcia-Blanco says. The Duke researchers have seen similar shifts from IIIb to IIIc in human prostate cancer cell lines in the lab, and plan to look at prostate cancer samples from patients in the near future.

These studies have been funded in part the American Cancer Society and the Duke Comprehensive Cancer Center. Funding from the Department of Defense grant is pending.

Possibilities of Rapamycin

The path from the lab to the clinic is a long one for potential new cancer treatments. Drugs can behave one way in cells, another way in laboratory mice, and still a third way in humans.

The art of translating lab work into a clinically useful drug takes not only skill, but also some luck. Consider, for example, a soil bacterium on Easter Island.

This bacterium produces a novel and complex molecule to kill fungi that compete with the bacterium for resources. This molecule, a small protein called rapamycin, turns out to be a potent immune-suppressing agent in humans and, after extensive testing, has recently been approved by the U. S. Food and Drug Administration to prevent organ rejection in kidney transplant patients.

While examining rapamycin in the lab, researchers noted that it also inhibited the growth of several types of cancer cells, including prostate cancer cells. Now Robert Abraham, Glaxo-Wellcome professor of molecular cancer biology in the department of pharmacology and cancer biology, and his research team are examining how rapamycin works.

Most of what is known about rapamycin has to do with its actions in immune system cells, but this provides a starting point for researchers like Abraham. Rapamycin combines with a small protein found in virtually all human cells, and the complex of the two then blocks the action of a critical signaling protein called mTOR, which stands for "mammalian target of rapamycin."

Abraham found that mTOR is involved in a pathway that normally relays growth signals from the cell surface to the protein-building machinery inside the cell.

As luck would have it, prostate cancer cells frequently contain genetic mutations that can turn on this mTOR-signaling pathway at an abnormally high level. Abraham and his colleagues have found that some prostate cancer cell lines can be controlled in the laboratory by rapamycin, but others can not. Now they're trying to detect differences between cells that respond and those that don't.

While a phase I trial with rapamycin in glioblastoma patients is ongoing at the Mayo Clinic in Rochester, Minn., Abraham's lab at Duke is looking for inhibitors of mTOR function that might work better than rapamycin itself for treating cancer. They've developed and patented a test they will use to screen new inhibitors of mTOR. If they find one, they'll have to start from scratch, evaluating it in cell studies, animal studies, and eventually human clinical trials.

These studies are funded by grants from the National Cancer Institute and Glaxo-Wellcome.

Rebuilding Chromosomes

A recently found enzyme called telomerase rebuilds the repetitious ends of chromosomes and plays a key role in cancer. Telomerase research at Duke may help solve some basic questions about how the disease gets started and keeps going.

Most normal cells don't have telomerase. As a result, each time a normal cell divides, DNA is lost from the ends of its chromosomes, a process that provides normal cells with a limited number of cell divisions. About 85 percent of cancers have telomerase turned on, allowing each cancer cell to rebuild its chromosomes and divide indefinitely.

When he was a postdoctoral researcher at the Whitehead Institute for Biomedical Research, Christopher Counter, now an assistant professor of pharmacology and cancer biology and of radiation oncology at Duke, helped clone the gene for the key part of telomerase. He and his colleagues were then able to make normal cells become cancerous by turning on just three genes: telomerase and two others called T-antigen and ras. Previous attempts with T-antigen and ras had given normal cells some cancerous characteristics, but it took the addition of telomerase to let the cells grow completely unchecked - the hallmark of cancer.

"The ability to make normal cells cancerous lets us follow the process of tumorigenesis in actual human cells," Counter explains. "Eventually we'll be able to dissect exactly what cellular steps are involved."

Counter will use his skills to make normal prostate cells become cancerous by giving them the same three genes. Scientists don't know exactly how prostate cells become cancerous or how the disease progresses, but they say Counter's work is likely to help them clarify some of these steps.

"We are searching for other molecules telomerase needs to work with in cancer cells, how the telomerase protein itself works, and how we can shut it off," Counter says.

These studies are funded by a Kimmel Scholar Award from the Sidney Kimmel Foundation for Cancer Research and grants from the V Foundation and Harley Davidson, Duke Comprehensive Cancer Center and the National Institutes of Health.

A Signal to Block

Dr. David Price, assistant professor of urology and of pharmacology and cancer biology, is looking for a good spot to build a road block.

Cells are a flurry of activity. Chemical messages are being sent at all times. Directions are being given to divide, to open up, to shut down or to change. These messages travel in a number of signal pathways, each of which is vital to cell life and some of which are overused in cancer cells.

Cell growth pathways, for example, stimulate the cell to start the process of dividing - a complex set of actions that include copying the chromosomes, lining everything up just right, and finally splitting into two new cells. Since cancer cells multiply without the same controls as normal cells, these cell growth pathways are expected to be important in how cancer gets started and keeps going.

Price is focusing his efforts on a growth pathway called the "extracellular regulated kinase" pathway (ERK), which is one of the major pathways that stimulates cell division.

With an award from the Association for the Cure of Cancer of the Prostate (CaPCURE), Price will look at ERK's role in prostate cancer cell lines in the laboratory and in animals to see if blocking the growth signal from this pathway will help control cell growth.

In addition to the CaPCURE award, funding also is provided by a Career Development Grant from the National Institutes of Health. Price also co-directs the Prostate Cancer Animal Core Facility, which was established to develop and promote prostate cancer research that can be translated from the lab to the clinic. The core facility provides support for several developing prostate cancer research programs and currently receives funds from the Duke Comprehensive Cancer Center, the department of surgery and private donations. The facility is also a central component of the pending Department of Defense grant.

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Wendy Demark-Wahnefried, associate research professor of urology, can be reached at (919) 681-3261.

Dr. Johannes Vieweg, assistant professor of urology, can be reached at (919) 684-9949.

Dr. Sal Pizzo, professor and chair of pathology, can be reached at (919) 684-3528.

Mark Dewhirst, professor of radiation oncology and assistant professor of pathology, can be reached at (919) 684-4180.

Dr. Mariano Garcia-Blanco, associate professor of genetics and associate professor of microbiology, can be reached at (919) 613-8632.

Robert Abraham, Glaxo-Wellcome professor of molecular cancer biology in the department of pharmacology and cancer biology, can be reached at (919) 613-8560.

Christopher Counter, assistant professor of pharmacology and cancer biology and of radiation oncology, can be reached at (919) 684-9890.

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