September 28, 2009
Radiation research has dual role
Alan 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