One of World's Deadliest Cancers Eliminated from Lungs
of Mice by New Drug, Radiation
UT Southwestern Medical Center finds success with
an investigative drug called BEZ235 in combination with low-dose
radiation
Researchers included Drs. Pier Paolo Scaglioni
(right) and Georgia Konstantinidou
Oct. 29, 2009 – One of the most dangerous of
cancers – non-small cell lung (NSCL) cancer – has been totally
eliminated from laboratory mice at UT Southwestern Medical Center by the
use of an investigative drug called BEZ235 in combination with low-dose
radiation. NSCL cancer is a leading cause of cancer-related deaths
worldwide.
In a study appearing in the October issue of Cancer
Research, UT Southwestern researchers found that if they administered
BEZ235 before they damaged the DNA of tumor cells with otherwise
nontoxic radiation, the drug blocked the pro-survival actions of a
protein called PI3K, which normally springs into action to keep tumor
cells alive while they repair DNA damage.
Researchers tested this novel therapeutic strategy
in mice transplanted with NSCL cancers obtained from patients.
They found that tumors in the mice treated with
BEZ235 alone were significantly smaller than those in mice not given the
drug. Although the tumors stopped growing, they did not die.
By contrast, tumors were completely eradicated in
mice treated with a combination of BEZ235 and radiation.
“These early results suggest that the drug-radiation combination might
be an effective therapy in lung cancer patients,” said
Dr. Pier Paolo Scaglioni, assistant professor of internal medicine
at UT Southwestern and senior author of the study.
The NSCL cancer cells often harbor mutations in a
gene called K-RAS. Patients with such K-RAS mutations typically are more
resistant to treatment with radiation and have a poor prognosis.
K-RAS mutations lead to the activation of networks,
or pathways, of several so-called signaling proteins, which in turn play
key roles in the regulation of tumor growth. One of these proteins,
called PI3K, is activated to keep cells alive that have sustained DNA
damage.
Several components of the signaling pathways,
including PI3K, have been investigated as possible anti-cancer drug
targets. The investigational drug BEZ235 is currently being tested in
clinical trials against PI3K and another signaling protein called mTOR.
“To date, no effective targeted therapy exists for
NSCL cancer tumors that harbor K-RAS mutations,” Dr. Scaglioni said.
Dr. Scaglioni and his team first tested the
effectiveness of BEZ235 alone and found that it inhibits the
proliferation of both lung cancer cells cultured in vitro and the growth
of lung-cancer tumors in mice.
“The results were striking, but we wanted to find a
strategy to precipitate cell death of these tumors,” said Dr. Georgia
Konstantinidou, a postdoctoral researcher at
UT Southwestern and the lead author of the study. “We did it with
radiation, which is a standard form of treatment for lung cancer.”
Dr. Scaglioni’s team exposed isolated cancer cells
to BEZ235 followed by low doses of radiation, which induced small breaks
in the DNA of the cells but otherwise would have no effect on cell
survival. When this type of DNA damage occurs, cancer cells rely on the
PI3K signaling pathway to survive while they repair their DNA.
“We stressed the cells in such a way that they
needed this signaling pathway to survive,” Dr. Scaglioni said. “Without
the PI3K response, they will die.”
When the researchers then treated the cells with
BEZ235, which blocks PI3K, the stressed NSCL cancer cells readily
underwent programmed cell death.
Dr. Scaglioni said that the next step is to use
BEZ235 or similar drugs in clinical trials on NSCL cancer patients as
well as other cancers, including pancreatic, colon and thyroid cancers,
where the PI3K signaling pathway also plays a role.
Other UT Southwestern researchers involved in the
study included Dr. Erik Bey, assistant instructor at the Harold C.
Simmons Comprehensive Cancer Center, Dr. Andrea Rabellino, postdoctoral
researcher in internal medicine, Dr. Katja Schuster, postdoctoral
researcher in internal medicine,
Dr. Adi Gazdar, professor of pathology in UT Southwestern’s Nancy B.
and Jake L. Hamon Center for Therapeutic Oncology Research, and
Dr. David Boothman, professor in the Simmons Comprehensive Cancer
Center and of pharmacology and radiation oncology. Researchers from the
University of Camerino in Italy and Novartis Pharma in Switzerland also
participated.
The work was supported by the National Institutes
of Health, American Cancer Society, Concern Foundation, Gibson
Foundation, Leukemia of Texas, U.S. Department of Energy and the
American Italian Cancer Foundation.
