Published online April 29 in PLoS ONE, the researchers report that if the agent continues to work well in further laboratory and preclinical studies, it may be the first prostate cancer drug specifically designed to stop cancer spread, or metastasis.
“This agent does not kill prostate cancer cells, but limits their ability to spread, which could be hugely beneficial in patients,” says the study’s lead investigator, Aykut Üren, M.D., an associate professor at Georgetown Lombardi. “This study is an early proof of principle that such an approach might be feasible in the clinic, but we have a lot of work to refine and test the drug.”
The agent, YK-4 279, was designed in the GUMC Drug Discovery Program, directed by Milton Brown, M.D., Ph.D., a co-author on the paper. YK-4 279 is also being investigated for the treatment of Ewing’s sarcoma and is expected to move quickly into a clinical study. Üren participated in the development of YK-4 279, an effort that was led by Georgetown Lombardi researcher Jeffrey Toretsky, M.D., also a co-author of this study.
Recent research has shown that 40 to 70 percent of prostate cancer cells express novel proteins when normal genes such as ETV1 and ERG break off from a chromosome and fuse in to a new location. These new genes produce proteins that push prostate cancer cells to become more aggressive and spread.
Noting that Ewing’s sarcoma is produced by a similar fusion gene, the researchers decided to see if their drug would work in prostate cancer cells.
They applied the agent to prostate cancer cells with chromosomal translocations that expressed either an ERG protein or an ETV1 protein and found that the YK-4 279 did inhibit functions of these proteins, which reduced their motility and invasiveness. Tests in cancer cells that did not have either translocation show the agent had no effect.
The researchers also found that although the male hormone androgen turns on genes involved in progression of prostate cancer, including these fusions genes, the presence or absence of androgen is not necessary for this agent to work.
“That means, if successful, YK-4 279 could work in androgen sensitive prostate cancer cells or in cancer that has become resistant to androgen treatment,” Üren says.
He says the agent will likely need to be reformulated for prostate cancer use since the fusion gene that causes the Ewing’s sarcoma is similar but not identical to ones in prostate cancer.
Additional co-authors of this paper include Said Rahim, Elspeth Beauchamp, Ph.D., and Yali Kong, Ph.D.
The study was funded by Georgetown Lombardi’s Cancer Center Support Grant from the National Cancer Institute, the Children’s Cancer Foundation, Go4the Goal, Dani’s Foundation, Alex’s Lemonade Stand Foundation, Liddy Shriver Sarcoma Initiative, Burroughs Wellcome Clinical Scientist Award in Translational Research, and the National Institutes of Health.
Georgetown University has patent applications pending on YK-4 279 in the United States, Canada, Europe, and Australia on which Uren, Brown, Kong and Toretsky are inventors.
About Georgetown Lombardi Comprehensive Cancer Center
The Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Lombardi is one of only 40 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington, DC, area. For more information, go to http://lombardi.georgetown.edu.
About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or “care of the whole person.” The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization (BGRO), which accounts for the majority of externally funded research at GUMC including a Clinical Translation and Science Award from the National Institutes of Health. In fiscal year 2009-2010, GUMC accounted for nearly 80 percent of Georgetown University’s extramural research funding.
Karen Mallet (media only)