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International study of advanced prostate cancer genome finds abundance of potential targets for drug therapy


Eliezer Van Allen, MD - largeEliezer Van Allen, MD

The first major effort to canvas the genomic landscape of advanced prostate cancer has revealed that many patients may carry some type of genetic abnormality that can be targeted with existing or potential drugs.

The finding, reported today by a Stand Up to Cancer-Prostate Cancer Foundation Dream Team in the May 21, 2015, edition of the journal Cell, is based on an analysis of tumor samples from 150 men with metastatic prostate cancer that no longer responded to standard hormone-blocking therapy. Eight institutions from the United States and Europe contributed tumor samples to the project.

“This study provides a strong argument that the genomics driving advanced prostate cancer is fundamentally different than primary prostate cancer, and that knowledge of these genomic differences may be immediately clinically actionable for patients with advanced disease,” said Eliezer Van Allen, MD, of Dana-Farber Cancer Institute, a first author of the study.

While previous studies have surveyed the genomic characteristics of tumors confined to the prostate gland, the new study is the first to focus on metastatic hormone resistant prostate cancers, which can be difficult to treat because they often develop resistance to standard treatments.

The researchers found that nearly all the tumors had at least one genetic aberration known to drive cancers. The most common, found in nearly two-thirds of the samples, were abnormalities in genes responsible for the androgen receptor – a cell structure that sends growth signals in response to the male hormone androgen. This wasn’t a surprise since the hallmark of castration-resistant disease is that it no longer responds to conventional androgen-blocking therapies. But many other aberrations were found as well.

About a quarter of patients had mutations in the DNA repair genes including BRCA1 or BRCA2 genes, which are known to increase the risk of breast and ovarian cancer. Drugs known as PARP inhibitors have already been approved for BRCA-positive ovarian cancer, suggesting that PARP inhibitors may prove effective in prostate cancers with this type of aberration.

In addition, the researchers found that 8 percent of patients had an inherited genetic alteration. This suggests that genetic counseling may be appropriate for patients with prostate cancer.

Philip W. Kantoff, MD - largePhilip Kantoff, MD

"This is a landmark paper in several respects,” said Philip Kantoff, MD, leader of the Lank Center for Genitourinary Oncology and chief of Solid Tumor Oncology at Dana-Farber, a senior author of the study. “It represents a model of collaboration between cancer centers, represents a monumental operational, technical and computational achievement and finally represents the value of precision medicine in finding actionable mutations.”

Other Dana-Farber contributors to the study include Levi Garraway, MD, PhD, a co-senior author, Mary-Ellen Taplin, MD, Mark Pomerantz, MD, and Massimo Loda, MD, director of Dana-Farber’s Center for Molecular Oncologic Pathology.

In the next phase of the study, researchers will genetically sequence tumor cells from at least 500 patients and follow the course of their disease. With this data in hand, researchers will track how patients with specific genetic abnormalities respond to certain treatments, improving doctors’ ability to treat the disease.

Additional authors are from the University of Michigan, the Broad Institute, the Beth Israel Deaconess Hospital, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York Presbyterian Hospital, the Fred Hutchinson Cancer Center, the University of Washington, the Institute of Cancer Research in London, the Royal Marsden NHS Foundation Trust in London, Beth Israel Deaconess Cancer Center, Brigham and Women’s Hospital, University of Trento, Italy, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, and Johns Hopkins School of Medicine.

Funding: Stand Up to Cancer-Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant; National Institutes of Health grants UM1 HG006508, U01 CA111275, P50 CA186786, P50 CA092629, P50 CA 097186, P01 CA163227, R01 CA116337, R01 CA155169, R01 CA092629, R01 CA155169, 1K08 CA188615; U.S. Department of Defense; Starr Cancer Consortium, A. Alfred Taubman Institute; American Cancer Society; Damon Runyon Cancer Research Foundation; Prostate Cancer Foundation; Movember Foundation, Prostate Cancer UK, Cancer Research UK, Department of Health in the UK.

8/26/2016 8:10:15 AM
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