• September 28, 2009
    Radiation research has dual role

    alan-dandrea.jpgAlan D'Andrea, MD 

    It's not a big leap, scientifically speaking, from improving radiation therapy for cancer patients to devising new diagnostic tools and therapies for people exposed to fallout from a radiological attack or accident.

    Which explains why a Center for Medical Countermeasures Against Radiation (CMCR) was established at Dana-Farber in 2004, and why it has been among the most productive of eight sister centers located across the country. Its researchers have not only helped develop the first-ever test for radiation exposure, but also found leads toward drugs that could reduce the harmful effects of radiation.

    Each CMCR is supported jointly by the National Institutes of Health and the Department of Homeland Security. Of the eight centers – located at such institutions as Columbia University Medical Center, Duke University School of Medicine, and the University of California David Geffen School of Medicine – only the Dana-Farber one is housed at a cancer center. For Alan D'Andrea, MD, and the Dana-Farber center's two other project leaders – Peter Sicinski, MD, PhD, and Stephen Elledge, PhD (based at Harvard Medical School) – its presence at Dana-Farber is hardly an anomaly.

    "Radiation kills cells and tumors by damaging their DNA," explains D'Andrea, chief of research in Dana-Farber's Department of Radiation Oncology and director of the CMCR at the Institute. "In the area of cancer research, we're seeking ways to make cancer cells more susceptible to radiation therapy by blocking DNA repair. At the CMCR, we're exploring how to improve DNA damage repair, so normal cells exposed to radiation from a nuclear attack or accident are more likely to survive. We're essentially approaching the same cell pathways and processes from two different angles."

    Toward a field-ready test

    The development of a "biodosimeter"  – a diagnostic test for measuring the amount of radiation that has passed through a person – played to the strengths of Dana-Farber researchers who study biomarkers, which are proteins or other substances in the body that indicate biological change. "We stimulated laboratory samples of human cells with different levels of radiation and then measured and identified the proteins that had been activated or modified as a result," D'Andrea says. "Through work at Stephen Elledge's lab our center found hundreds of proteins that underwent such changes, and we can now screen people's blood for those changes to determine whether they've been exposed to radiation." Additional work is necessary before the biodosimeter is ready for mass use, but the basic elements are now in place.

    A second major goal of the CMCR program – discovery of agents that can lessen the effects of radiation – is drawing closer as well. Sicinski, who specializes in the study of cell proliferation, is exploring whether blocking certain components of cell cycle machinery protects mice from the toxic effects of radiation. Sicinski and his colleagues are screening chemical compounds that inhibit particular enzymes involved in cell cycle progression, making them promising drug candidates.

    "Many cell cycle inhibitors are already used in clinical trials for anticancer therapy," Sicinski says. "So they could be immediately used to protect cells from radiation-induced cell death." The researchers are now exploring the optimal point at which cell division should be shut off, and for how long.

    D'Andrea, meanwhile, is taking another approach to radiation-countering drugs. "Much of the harm that radiation does to cells is the result of the generation of active oxygen radicals [unstable groups of oxygen atoms]," he remarks. "We're investigating whether oxygen-limiting drugs can reduce these free radicals and provide protection to cells."

    For members of the Dana-Farber CMCR, the advantages of being based at a cancer center are clear. One is the potential that their work will improve cancer treatment. "For people who receive radiation treatment for cancer, a biodosimeter may be used to ensure that patients are receiving the intended amount of radiotherapy – that radiation-delivery machinery performs as advertised," D'Andrea says.

    A second advantage is scientific. "Biomarkers are used throughout cancer medicine and research to identify the type of cancer a patient has, and the most effective therapy for that specific variety," D'Andrea continues. "Having that expertise at Dana-Farber has been critical in the ongoing development of our biodosimeter." Thirdly, the availability of high-powered drug screening facilities at Dana-Farber and Harvard Medical School has sped the search for new or existing drugs that can safely alleviate the harmful effects of radiation.

    – Rob Levy
    Robert_Levy@dfci.harvard.edu 

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