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Dr. Evan Keller is the principal investigator for a grant from National Cancer Institute.

U-M research team receives $7.4 million to study spread of prostate cancer to bones.

National Cancer Institute grant will fund collaboration of U-M Comprehensive Cancer Center and the
School of Dentistry.

ANN ARBOR, MI -- Over eight in ten men afflicted with advanced prostate cancer will face the inevitability of bone metastasis - the cancer spreading to their bones, and the prospect of debilitating pain, fractures, impaired movement and neurological complications. Yet despite these striking statistics and the serious complications posed by bone lesions, science has responded with remarkably little research to determine why the skeleton is the most likely target for the movement prostate cancer, or what strategies might eventually be developed to combat this route of progression of the disease.

In response to the scarcity of insight into this important area, the National Cancer Institute's Prostate Cancer Progress Review Group has awarded a grant totaling $7.4 million over 5 years to a group of collaborators from the University of Michigan, led by principal investigator Evan T. Keller, M.P.V.M., D.V.M., Ph.D. Together, they will undertake four different research projects, each intended to define the cellular and molecular mechanisms that lead to prostate cancer skeletal metastases.

The group was successful in obtaining the grant in part because of the novel partnership they have formed. Investigators with expertise in prostate cancer research, including Keller, associate professor of urology and pathology, Kenneth J. Pienta, M.D., professor of internal medicine and urology and others from the U-M Comprehensive Cancer Center will team with experts in bone metabolism including Russel Taichman, D.M.D., D.M.Sc., associate professor of periodontics, prevention and geriatric dentistry and Laurie McCauley, D.D.S., Ph.D., chair and professor of periodontics, prevention and geriatrics, both from the U-M School of Dentistry.

The underlying theory driving each of the program's four projects is equally novel: Keller's team asserts that there is "crosstalk" between the microenvironment of the human bone structure and that of prostate cancer cells that fosters the development of prostate cancer bone metastasis. In other words, there is some predisposition of prostate cancer to settle in bones which depends on a reciprocal interaction between the skeletal system and some specific property or properties of prostate cancer cells.

Project #1, directed by Taichman, will explore how prostate cancer cells find and adhere to bone marrow. Project #2, headed by Pienta, will examine a specific molecule recently identified in Pienta's lab called protease-activated receptor-1 (PAR-1) to determine how it might promote the movement of prostate cancer cells and whether it may play a role in encouraging those cells to target bone sites. Project #3, directed by Keller, will investigate possible ways that proteins involved in the development of bone structure may intercede in the metastasis of prostate cancer to the bones. Project #4, led by McCauley, will look at a specific hormone-related protein called PTHrP and its potential contribution to developing bone lesions.

Completing these projects will require a remarkable team effort. Keller will create three research "cores" to support the collaboration. An Administrative Core will coordinate the reporting, evaluation, communications and biostatistics required. A Bone Core will provide expertise with bone techniques including bone histomorphometry to measure bone biological parameters, and histology, radiography and bone densitometry. An Animal Core will supervise the required mouse animal models, providing input into animal model design and interpretation of results. In addition, the program will benefit from direct interaction with the U-M Cancer Center's Prostate Cancer Specialized Program in Research Excellence (SPORE) Tissue Pathology Core to provide immunohistochemistry services, as well as input from the Cancer Center's Connective Tissue Oncology Program.

Keller hopes that this expansive program will yield understanding of the interaction between prostate cancer cells and the skeletal structure, and that eventually the team's findings will translate into the clinical setting to help patients suffering from advanced prostate cancer. "This program is truly a team effort leveraging the best of basic and clinical science from multiple disciplines. I believe bringing this team together to focus on the serious problem of bone metastasis - which effects most men with advanced prostate cancer - will lead us to significant advances in our understanding of how these cancer cells spread. We hope our findings will guide us to new therapies to treat bone metastasis."

For more information on advanced prostate cancer, call the U-M Comprehensive Cancer Center's Cancer AnswerLine at 800-865-1125.

See also U-M research team receives $7.4 million to study spread of prostate cancer to bones.