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PUBLIC RELEASE DATE:
10-Apr-2014

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Contact: Vanessa Wasta
wasta@jhmi.edu
410-614-2916
Johns Hopkins Medicine

Enzyme revealed as promising target to treat asthma and cancer

In experiments with mice, Johns Hopkins Kimmel Cancer Center scientists have identified an enzyme involved in the regulation of immune system T cells that could be a useful target in treating asthma and boosting the effects of certain cancer therapies.

In research described online April 6 in Nature Immunology, the investigators show that mice without the enzyme SGK1 were resistant to dust mite-induced asthma. And mice with melanoma and missing the enzyme, developed far fewer lung tumors—less than half as many—than mice with SGK1.

"If we can develop a drug that blocks the enzyme in a way that mimics what happens when the enzyme is missing, we would not only have a treatment to inhibit asthma, but also a drug that could be used in conjunction with other experimental therapies aimed at helping the immune system fight cancer," said Jonathan D. Powell, M.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center.

The unusual dual potential of an SGK1-blocking compound stems from the enzyme's role in a key pathway linked to T cells, which act as either "generals" of the immune system by directing how the system works, or "soldiers" that seek and destroy foreign cells.

Powell and his colleagues decided to look at SGK1 because it works along the same pathway of a protein called mTOR, a focus of their previous research. The mTOR pathway helps T cells decipher signals from their environment, and prompts the cells to transform into specific T cell types.

As part of this pathway, SGK1 dials down production of a signaling protein called interferon-gamma. When SGK1 is inactive, T cells produce increased amounts of interferon-gamma that appear to be useful in fighting tumor cells.

Powell said that a SGK1-blocking drug might be used in conjunction with other cancer immunotherapies as a sort of booster medication to enhance their effects. Experimental cancer immunotherapies, including vaccines and so-called checkpoint blockade inhibitors, are the focus of intense research within the past few years, he added.

The researchers also discovered that SGK1 promotes the production of T helper 2 cells, which become overactive in asthma and other allergies in a sort of runaway case of inflammation. Finding a drug that could shut down SGK1 could help block the inflammation that causes asthma and other allergic reactions.

By untangling the different effects of SGK1, Powell said, his team has advanced efforts to fine-tune immune responses in patients. "We're not suppressing or exacerbating the immune system, we're regulating it," he noted. "We're regulating it to do exactly what we want it to do."

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Other scientists involved in the study were Emily Heikamp, Chirag H. Patel, Sam Collins, Adam Waickman, Min-Hee Oh, Im-Hong Sun, Peter Illei and Maureen R. Horton from Johns Hopkins; Archna Sharma and Jyoti Sen from the National Institutes of Health; and Aniko Naray-Fejes-Toth and Geza Fejes-Toth from Dartmouth Medical School.

The work was supported by the National Institutes of Health (R01 AI77610, DK 41481, DK 58898); the American Asthma Foundation; the American Medical Association Seed Foundation Grant; and the Flight Attendant Medical Research Institute.

On the Web: Nature Immunology

JOHNS HOPKINS MEDICINE

Johns Hopkins Medicine (JHM), headquartered in Baltimore, Maryland, is a $6.7 billion integrated global health enterprise and one of the leading health care systems in the United States. JHM unites physicians and scientists of the Johns Hopkins University School of Medicine with the organizations, health professionals and facilities of The Johns Hopkins Hospital and Health System. JHM's mission is to improve the health of the community and the world by setting the standard of excellence in medical education, research and clinical care. Diverse and inclusive, JHM educates medical students, scientists, health care professionals and the public; conducts biomedical research; and provides patient-centered medicine to prevent, diagnose and treat human illness. JHM operates six academic and community hospitals, four suburban health care and surgery centers, more than 38 primary health care outpatient sites and other businesses that care for national and international patients and activities. The Johns Hopkins Hospital, opened in 1889, was ranked number one in the nation for 21 years by U.S. News & World Report.

Media Contacts:
Vanessa Wasta, 410-614-2916, wasta@jhmi.edu
Amy Mone, 410-614-2915, amone@jhmi.edu



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