Why does prostate cancer become deadly?

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Why does prostate cancer become deadly?

NCI grants totaling $23 million go to Northwest centers to seek answers; Fred Hutchinson to lead consortium of 50 Seattle, Vancouver scientists

Oct. 3, 2002
Dr. Janet Stanford

Dr. Janet Stanford of Fred Hutchinson, along with Dr. Paul Lange of the University of Washington, lead the Pacific Northwest prostate-cancer SPORE consortium.

Photo by Todd McNaught

Understanding how and why prostate cancer can turn deadly is key to developing therapies that may effectively treat men with recurrent or advanced prostate cancer, for which there is no cure.

To foster such understanding, the National Cancer Institute has awarded $12.7 million to Fred Hutchinson to lead a multi-center, five-year investigation into the genetic mechanisms of prostate-cancer progression.

Known as the Pacific Northwest Prostate Cancer Research SPORE (Specialized Program of Research Excellence), the initiative will involve more than 50 investigators in Seattle and Vancouver, B.C.

Other participating institutions in Seattle are the University of Washington and the Institute for Systems Biology. Vancouver partners are the University of British Columbia and its affiliate, The Prostate Centre at Vancouver General Hospital.

The grant comes on the heels of another prostate-cancer research coup for Seattle researchers. In July, the UW was awarded a $10.5 million NIH grant to lead Fred Hutchinson and the Institute for Systems Biology (co-founded by former UW geneticist Dr. Leroy Hood) in a five-year investigation into why prostate cancer metastasizes, or spreads, to the bone.

Unprecedented support

Together, the two hefty grants, totaling $23.2 million, give area researchers unprecedented opportunities to better understand prostate cancer and develop improved therapies, particularly for men with recurrent or advanced disease.

The long collaboration among these institutions - themselves major contributors to prostate-cancer research - was key to getting the SPORE grant, said principal investigator Dr. Paul Lange of the Public Health Sciences Division and professor and urology chair at UW School of Medicine.

"This highly competitive award exemplifies the high caliber of prostate-cancer research among the major medical-research institutions in the Northwest and the significant collaborations among researchers from the participating institutions," Lange said.

During the past decade, for example, Seattle prostate-cancer investigators have met regularly to understand the hereditary and lifestyle factors behind prostate cancer and develop technologies to unravel the genetic mechanisms of the disease. Fruits of their labor include mapping the region of a gene associated with inherited prostate cancer and primary brain cancer, as well as better understanding the genes expressed in the more common forms of prostate cancer.

"The close relationship between these institutions and our long-standing track record of success was crucial to getting the grant," echoed co-principal investigator Dr. Janet Stanford of PHS and director of its Prostate Cancer Research Program.

"There hasn't been a lot of improvement in the survival of men with advanced prostate cancer over the past 30 years, so to focus on understanding the factors that may contribute to progression from clinically less aggressive to more aggressive disease is important if we're to develop therapies that will effectively treat these men," said Stanford, also a professor of epidemiology in the UW School of Public Health and Community Medicine.

Overarching goal

The overarching goal of the consortium is to bring more quickly and efficiently laboratory discoveries to Northwest patient bedsides. Clinical partners will recruit and enroll patients for research studies to test the therapies that emerge.

They will include the Seattle Cancer Care Alliance (the oncology patient-care arm of Fred Hutchinson, UW Academic Medical Center and Children's Hospital and Regional Medical Center) and the Veterans Affairs Puget Sound Health Care System in Seattle; the Oregon Cancer Institute/Oregon Health & Science University in Portland, Ore.; and Vancouver General Hospital/University of British Columbia.

Consortium plans four projects

Improving the treatment options for men faced with recurrent prostate cancer that no longer responds to androgen-deprivation therapy is the unifying mission behind the SPORE consortium's four scientific projects.

All four projects seek to apply the insights of laboratory and epidemiological research to better understand how and why prostate cancer spreads.

Here are the four:

Identifying genetic variants linked to prostate-cancer progression and mortality

This study aims to identify genetic variants that are linked to prostate-cancer recurrence and mortality. The goal is to develop a simple blood test to determine which prostate-cancer patients are most likely to progress to advanced disease.

Researchers will follow more than 700 Seattle-area men, all of whom were diagnosed with prostate cancer before age 65, to see if those who relapse share common genetic markers of disease progression.

Leaders: Drs. Janet Stanford, Fred Hutchinson PHS, and David Penson, assistant professor of surgery, UW School of Medicine.

Understanding the genetic differences between men who relapse and men who remain cancer-free after initial therapy for localized prostate cancer

Previous studies have found that many men with early-stage prostate cancer, even those cured with localized therapy such as surgery or radiation, have prostate-cancer cells in their blood and bone marrow early in the disease process. It is not known why some of these circulating cells turn into deadly, metastatic cancer while others die or remain dormant.

This study will examine blood samples from men who undergo surgery for early-stage prostate cancer to determine the genetic differences between those who remain cancer-free and those whose cancer recurs. The goal is to develop a genetic screening tool to identify which men are most likely to relapse and may benefit from more aggressive therapy upon initial diagnosis.

Leaders: Drs. Robert Vessella, professor and associate chair of urology, and William Ellis, assistant professor of urology, both of the UW School of Medicine; and Barbara Trask, director, Fred Hutchinson Human Biology Division.

Developing new treatments for men with advanced prostate cancer who no longer respond to androgen-deprivation therapy

The goal is to develop new treatments for men with advanced prostate cancer who no longer respond to androgen-deprivation therapy.

The idea is to harness antisense technology, which inhibits gene expression, to coax hormone-insensitive prostate-cancer cells to commit suicide, a process called apoptosis, or programmed cell death. Such antisense drugs, when combined with novel chemotherapeutic agents or combinations of existing drugs, also may block the cellular processes that allow cancer to grow.

Leaders: Drs. Martin Gleave, professor of surgery and director of clinical research, and Colleen Nelson, assistant professor of surgery and gene-array facility head, both of the University of British Columbia/The Prostate Centre at Vancouver General Hospital.

Understanding the molecular biology of prostate cancer through all stages of its progression

This project will analyze gene and protein expression in the entire spectrum of prostate tumors, from those clinically localized and slow-growing to those advanced and highly aggressive.

The goal is to create a genetic blueprint to help understand the molecular biology of prostate cancer at all stages of its progression. A particular focus will be to understand mechanisms that cause tumors to progress from androgen-dependent and treatable to androgen-independent and drug-resistant. Deciphering the molecular pathways that allow disease progression could help identify new drug targets and genes linked to tumor metastasis.

Leaders: Drs. Leroy Hood, co-founder and president, Institute for Systems Biology, and UW affiliate professor of bioengineering, immunology, computer science/engineering; and Pete Nelson of Fred Hutchinson Human Biology and Clinical Research and assistant professor of medicine and biotechnology, UW School of Medicine.

The five cores of the SPORE

An infrastructure of SPORE-funded research cores will provide resources and expertise in administration, bioinformatics, biostatistics, specimen collection and tissue banking, and clinical-trial design, recruitment and management. Here are the cores:

Leadership and administration

Leader: Dr. Paul Lange, UW; co-leader: Dr. Janet Stanford, Fred Hutchinson. Operates internal and external advisory boards and committees that oversee the scientific direction and progress of the SPORE.

Tissue and specimens

Leader: Dr. Robert Vessella, professor of urology; co-leader: Dr. Lawrence True, associate professor of pathology, both of UW. Handles specimen collection, storage, distribution and clinical/research-information dissemination.


Leader: Dr. Ruth Etzioni, Fred Hutchinson. Links study design with data collection and analysis and helps design studies that feasibly address questions of scientific interest, are amenable to statistical analysis and yield statistically valid and interpretable results.

Informatics and gene expression

Leader: Dr. Pete Nelson, Human Biology and Clinical Research; co-leader: Dr. Nigel Clegg, senior fellow, both of Fred Hutchinson. Provides gene-chip technology and data-analysis tools to facilitate large gene-expression studies.

Clinical practices

Leader: Dr. Celestia Higano, associate professor, medical oncology, UW. Quickly brings promising findings into the clinic by providing tissue samples for analysis, establishing a unified database and designing and conducting trials. The goal is to facilitate data flow between the laboratory and clinic. Works with advocacy group to engage patients in SPORE activities.

Do you have a pilot project for prostate-cancer SPORE?

The SPORE grant will fund up to four pilot projects each year to support innovative translational research to improve prostate-cancer survival.

Priority for funding will go to proposals that are multidisciplinary, likely to lead to submission of applications for independently funded investigations, and have translational potential - a probability of leading to new methods to prevent, diagnose, or treat prostate cancer.

New applications will be given higher priority than submissions for continuation of ongoing projects. Priority also will be given to projects with budgets of $50,000 or less.

Eligible to apply are investigators at the center, the University of Washington, the University of British Columbia, the Institute for Systems Biology and others with an affiliation with the Prostate Cancer Research Program or the SPORE.

Applications should include a two- to three- page description of the proposed study, including background/rationale, hypothesis, specific aims, and research design/methods, a one-year budget on a standard NIH budget form (PHS 398 page 4), and a brief budget justification.

Applications should be received by Monday, Nov. 18. Send 10 copies to: Janet L. Stanford, c/o Megan Fairweather, PNW Prostate Cancer SPORE, mailstop MW-814. For more information, call 206-667-2716, fax 206-667-2717 or e-mail mfairwea@fhcrc.org. Notifications will be sent in mid-December/ Funding is pending Institutional Review Board approval.


Prostate cancer is the most common male cancer; an estimated 1.5 million Americans live with the disease, which affects one in six and is the second-leading cause of death from cancer in men. An estimated 189,000 men will be diagnosed this year and about 30,200 will die of it, according to the American Cancer Society.

Due to the prevalence of prostate-specific antigen, or PSA, screening, most men are diagnosed before the disease has spread beyond the prostate. Only 6 percent of men first are diagnosed with advanced prostate cancer that has migrated to the bones.

Initial diagnosis of advanced prostate cancer is rare, but recurrence after primary therapy is not. Population-based studies have found that among men under age 70 who are diagnosed with localized prostate cancer, between 20 percent and 30 percent will develop a recurrence, and many will die from the disease. Once the disease spreads to the bone, the median survival is 36 months.

Male hormones, or androgens, are known to fuel prostate-cancer growth, so current treatments for advanced prostate cancer focus on slowing the progression of the disease through surgical or chemical castration, also known as androgen-deprivation therapy. Prostate cancer consists of both "hormone-sensitive" and "hormone-insensitive" cells, and everyone's ratio of such cells is different.

Eliminating the body's major source of androgens, such as testosterone, interrupts the pathway of hormone production that speeds the growth of hormone-sensitive cancer cells. While such therapy increases the length of life, it is not considered a cure, as androgen deprivation is effective only in controlling the growth of the cancer cells that feed on male hormones. Eventually, these hormone-sensitive cells are crowded out by hormone-insensitive cancer cells, which don't depend on male hormones to proliferate.

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