SEATTLE – The National Cancer Institute, a branch of the National Institutes of Health, has awarded an $11.3 million, five-year competitive grant renewal to Fred Hutchinson Cancer Research Center for its continued leadership of a multi-center prostate cancer research consortium, which was first funded in 2002.
Known as the Pacific Northwest Prostate Cancer SPORE (SPORE is short for Specialized Programs of Research Excellence), the consortium aims to unravel the molecular mechanisms underlying the development and progression of prostate cancer and to develop new therapeutic strategies that use precision-medicine approaches to improve survival and reduce treatment-related side effects. "Precision medicine" is guided by the unique genetic and molecular signatures of each patient's cancer to deliver the most effective treatment.
The consortium, which involves more than 50 researchers in Seattle, Portland and Vancouver, B.C., has been led by Fred Hutch since it was established in 2002 with a $12.7 million, five-year NCI grant. An additional five-year, $11.8 million competing NCI grant renewal was awarded to the Hutch in 2007, reinforcing the reputation of the Pacific Northwest consortium as a major force in prostate cancer research.
The principal investigator of the consortium since 2007 has been Peter S. Nelson, M.D., a member of the Human Biology Division at Fred Hutch, and the co-principal investigator since its establishment has been Janet L. Stanford, Ph.D., a member of the Fred Hutch Public Health Sciences Division. Nelson and Stanford also serve as co-directors of the Fred Hutchinson/University of Washington Cancer Consortium Program in Prostate Cancer Research.
The Pacific Northwest Prostate Cancer SPORE continuation grant represents a coordinated effort between four institutions, each with established programs and strengths in translational prostate cancer research. In addition to Fred Hutch, participating centers include the University of Washington; the University of British Columbia and its affiliate, the Prostate Centre of Vancouver General Hospital; and Oregon Health & Science University.
The history of collaboration among these institutions was crucial for receiving this competing grant renewal, Nelson said.
"The respective teams of clinicians and researchers at these institutions bring the considerable scientific depth, breadth, creativity and vision required for our collective goal of reducing the morbidity and mortality associated with prostate cancer," he said.
"Our integrated, bench-to-bedside approach involves basic, clinical and population sciences research teams that are devoted to exploring a fundamental understanding of cancer biology, including molecular genetics and genomics."
Prostate cancer is the most frequently diagnosed solid tumor in men and the second-leading cause of cancer deaths. Since the last SPORE grant renewal in 2007, Nelson and colleagues estimate that more than a million men have been diagnosed with the disease in the U.S. and more than 150,000 have died of metastatic, or advanced, prostate cancer – a disease that is often accompanied by prolonged and severe suffering.
"The absolute number of men dying from prostate cancer increased by about 25 percent between 2007 and 2011," Stanford said, noting that the U.S. death toll now approaches 30,000 men a year. "When examining the trends in prostate cancer mortality, it is clear that our current 'optimal' therapies for advanced prostate cancer are limited, with relative five-year survival rates that have hovered around 30 percent for the past three decades."
The consortium aims to focus on finding molecular and other factors associated with the risk of prostate cancer recurrence and progression as well as its response – and resistance – to treatment. To this end, it is structured around five research projects, some ongoing and some new.
Project 1: Molecular predictors of prostate cancer progression and mortality – This ongoing project seeks to discover inherited genetic and tumor epigenetic variations associated with prostate cancer progression and mortality in a population-based cohort of patients. The goal is to identify biomarkers of aggressive prostate cancer that will help distinguish at the time of diagnosis which patients face a higher probability of having aggressive as opposed to indolent, or non-life-threatening, disease.
Initial progress includes the identification of a panel of 22 single-nucleotide polymorphisms, or SNPs, associated with a high risk of prostate cancer-specific mortality, including five SNPs that have been validated in an independent prostate cancer patient cohort to be associated with a 50 percent higher risk of dying from the disease.
SNPs, pronounced "snips," are single-letter genetic variations in the four-letter DNA alphabet that play a role in the development and progression of disease.
Stanford co-leads this project with Dan Lin, M.D., a joint associate member of the Fred Hutch Public Health Sciences Division, professor of urology and director of urologic oncology at the UW School of Medicine.
Project 2: Targeting lysine-specific demethylase 1 (LSD1) in prostate cancer – This new project aims to test the hypothesis that a gene called LSD1 promotes the survival of prostate cancer cells and the progression to lethal disease by causing tumors to become androgen independent, which means they no longer respond to androgen-deprivation or castration therapy. The goal is to understand the mechanisms by which LSD1 promotes prostate cancer proliferation and progression, a necessary step for developing treatments to disable this gene.
The co-leaders of this project are Joshi Alumkal, M.D., an associate professor of medicine at Oregon Health & Science University; and Tomasz Beer, M.D., the Grover C. Bagby Endowed Chair for Prostate Cancer Research, professor of medicine, hematology and medical oncology and director of the Prostate Cancer Research Program at OHSU.
Project 3: Targeting SEMA3C in castration-resistant prostate cancer – This new project is focused on defining and targeting pathways that drive advanced prostate cancer. The goal is to define the mechanisms of a gene called SEMA3C in promoting resistance to androgen-deprivation therapy in an effort to develop and test a new therapy that targets the SEMA3C pathway in a preclinical model and, ultimately, in a phase 1 human clinical trial.
The co-leaders of this project are Christopher Ong, Ph.D., a research scientist with the Vancouver Prostate Centre and assistant professor of surgery and urologic sciences at the University of British Columbia; and Martin Gleave, M.D., B.C. Leadership Chair in Prostate Cancer Research, University of British Columbia Distinguished Professor and executive director of the Vancouver Prostate Centre.
Project 4: Clinical development of therapeutic strategies targeting DNA damage responses in the prostate tumor microenvironment – This new project will conduct preclinical and clinical trials to test the hypothesis that inhibiting DNA damage in the tumor neighborhood, or "microenvironment," will enhance the response of prostate tumors to treatment. "Cancer cells inside the body live in a very complex environment or neighborhood," said Nelson, co-director of the project. "Where the tumor cell resides and who its neighbors are influence its response and resistance to therapy."
"Our preliminary findings indicate that the tumor microenvironment can influence the success or failure of more precise therapies," Nelson said. In other words, the same cancer cell, when exposed to different neighborhoods, may have very different responses to treatment.
The co-leader of the project along with Nelson is Robert Bruce Montgomery, M.D., associate professor of medical oncology at UW School of Medicine and an affiliate member of the Fred Hutch Clinical Research Division.
Project 5: Exploiting mechanisms of response and resistance to next-generation androgen pathway antagonists – The overarching goal of this ongoing project is to define mechanisms of treatment resistance, identify biomarkers of treatment response and develop new treatment strategies for patients with advanced, castration-resistant prostate cancer who fail to respond to next-generation androgen-blocking drugs such as abiraterone.
Initial results have demonstrated that advanced prostate cancers that are resistant to androgen-deprivation therapy have high concentrations of intratumor androgens, a form of testosterone. This finding led to the development of next-generation androgen-pathway inhibitors such as abiraterone. Preclinical studies of these drugs have identified new mechanisms of treatment resistance that may lead to the development of new classes of drugs.
Co-leaders of this project are Elahe Mostaghel, M.D., Ph.D., an assistant member of the Clinical Research Division at Fred Hutch; and Stephen Plymate, M.D., professor of medicine in the Division of Gerontology and Geriatric Medicine at UW.
"The overall translational research objective of the Pacific Northwest Prostate Cancer SPORE is to understand and attack the deadly form of prostate cancer to reduce death and suffering caused by this disease," Nelson said. "The portfolio of projects is designed to improve prostate cancer prognosis and treatment response through approaches that are focused at the level of the individual patient, individual tumor and individual therapy."
The five projects will be supported by an infrastructure of SPORE-funded research cores that will provide resources and expertise in a variety of areas, including leadership and administration, biostatistics and clinical trial design, and the development of new model systems and biospecimen resources.
"Unique aspects of the SPORE include resources for recruiting young scientists and physicians for careers in prostate cancer research, and providing support for early stage, 'high-risk, high-gain' pilot projects that have the potential to transform our understanding and treatment of this extraordinarily common disease," Nelson said.
At Fred Hutchinson Cancer Research Center, home to three Nobel laureates, interdisciplinary teams of world-renowned scientists seek new and innovative ways to prevent, diagnose and treat cancer, HIV/AIDS and other life-threatening diseases. Fred Hutch's pioneering work in bone marrow transplantation led to the development of immunotherapy, which harnesses the power of the immune system to treat cancer with minimal side effects. An independent, nonprofit research institute based in Seattle, Fred Hutch houses the nation's first and largest cancer prevention research program, as well as the clinical coordinating center of the Women's Health Initiative and the international headquarters of the HIV Vaccine Trials Network. Private contributions are essential for enabling Fred Hutch scientists to explore novel research opportunities that lead to important medical breakthroughs. For more information visit http://www.fredhutch.org or follow Fred Hutch on Facebook, Twitter or YouTube.
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