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NEW YORK, June 24, 2010?A unique collaboration among physician-scientists at Memorial Sloan-Kettering Cancer Center (MSKCC) has yielded the most comprehensive genomic analysis of prostate cancer to date. “Genomic studies in other cancer types have resulted in new drug targets and strategies to classify patients into clinically meaningful subgroups that improve treatment decisions,” said senior study author Charles Sawyers, Chair of the Human Oncology and Pathogenesis Program at MSKCC and a HHMI investigator. “This first -ever database of its type brings us one step closer to achieving that goal in prostate cancer.”

The study, published early online on June 24 in the journal Cancer Cell, provides a previously unavailable genomic analysis whose scope and size offers new insight leading to more effective diagnostic tests as well as future treatment options for prostate cancer patients.

“We have used all of our expertise and resources to complete a large-scale study of the changes in the genomes of patients’ prostate cancers,” says Dr. Sawyers, who explains that prostate tumor cells are very difficult to work with despite the fact that prostate cancer is the most common cancer in men. Consequently, there have been fewer genomic studies in prostate cancer compared to other tumor types such as lung cancer. “The ability to collect and analyze these tumor samples is a testament to the collaboration and expertise across many disciplines.”

The MSKCC team, composed of members of the Human Oncology and Pathogenesis Program, urology, medicine and genitourinary oncology services, pathology, computational biology, and statistics departments, used an integrated, comprehensive approach to analyze 218 primary and metastatic samples and 12 cell lines. All samples were procured from patients treated by radical prostatectomy at MSKCC. The analysis revealed a much higher frequency of alterations in the androgen receptor pathway than previously suspected. Also, the pattern of DNA copy number alterations identified defined subsets of low-and high-risk disease beyond what is revealed by Gleason score.

“One of the holy grails of prostate cancer is to identify which tumors need to be aggressively treated and which don’t,” said Dr. Sawyers. “Ultimately, what we have learned could lead to the creation of a genetic-based test to determine which prostate cancers might become more virulent and require aggressive treatment and which tumors may not.” According to Dr. Sawyers, “This data clarifies the role of several known cancer pathways and provides important clues into others. We have gained insight into the importance of androgen receptor status?and why some men respond to hormone therapy and others don’t.”

The MSKCC genetic and clinical outcome data is publically available and represents a valuable resource to the cancer research community. The computational biology department has created the user-friendly, Web-based portal: http://awabi.cbio.mskcc.org/portal.

The research was supported in part by the MSKCC Prostate SPORE CA092629 and by the David H. Koch Foundation and is dedicated to the memory of MSKCC researcher William Gerald who initiated this project.

Memorial Sloan-Kettering Cancer Center is the world’s oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose, and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide. For more information, go to www.mskcc.org.

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	VIDEO: This is a tutorial on how tissue-engineered rat lung is transplanted. Click here for more information.

VIDEO:
This video shows how lung tissue is engineered.

They then cultured a combination of lung-specific cells on the extracellular matrix, using a novel bioreactor designed to mimic some aspects of the fetal lung environment. Under the fetal-like conditions of the bioreactor, the cells repopulated the decellularized matrix with functional lung cells. When implanted into rats for short intervals of time (45-120 minutes), the engineered lungs exchanged oxygen and carbon dioxide similarly to natural lungs.

Lead author Laura Niklason, M.D., Ph.D., professor and vice-chair of the Departments of Anesthesiology and Biomedical Engineering at Yale University and a member of Yale Medical Group, said, “We succeeded in engineering an implantable lung in our rat model that could efficiently exchange oxygen and carbon dioxide, and could oxygenate hemoglobin in the blood. This is an early step in the regeneration of entire lungs for larger animals and, eventually, for humans.”

The team found that the mechanical characteristics of the engineered lungs were similar to those of native tissues and, when implanted, were capable of participating in gas exchange. “Seeded and cultured epithelium displays remarkable hierarchical organization within the lung matrix, while seeded endothelial cells efficiently repopulate the lung vasculature, Niklason said.

The Yale team says this is an important first step, but a great deal more research must be done to see if fully functional lungs can be regenerated in vitro, implanted and sustained in their functioning. Niklason says that for this technology to be applicable to patients, it is likely that years of research with adult stem cells will be needed to repopulate lung matrices and produce fully functional lungs.

Other authors are Thomas H. Petersen, Ph.D., Duke University; and Elizabeth A. Calle, B.S., Liping Zhao, M.S., Eun Jung Lee, Ph.D., Liqiong Gui, Ph.D., MichaSam B. Raredon, Kseniya Gavrilov, B.S., Tai Yi, M.D., Zhen W. Zhuang, M.S., M.D., Christopher Breuer, M.D., and Erica Herzog, M.D., Ph.D., of Yale University.

Funding was provided by the Yale School of Medicine Department of Anesthesiology and the National Institutes of Health.

Citation: Science Express, June 24, 2010