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.
NSCL cancer is a leading cause of cancer-related deaths worldwide. The 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.
Visit www.utsouthwestern.org/cancercenter to learn more about UT Southwestern’s clinical services for cancer.
Dr. Pier Paolo Scaglioni -- http://www.utsouthwestern.edu/findfac/professional/0,2356,86271,00.html
Dr. Pier Paolo Scaglioni | Newswise Science News
Illinois team develops first of a kind in-vitro 3D neural tissue model
12.12.2019 | University of Illinois College of Engineering
Safer viruses for vaccine research and diagnosis
12.12.2019 | University of Queensland
More than one hundred and fifty years have passed since the publication of James Clerk Maxwell's "A Dynamical Theory of the Electromagnetic Field" (1865). What would our lives be without this publication?
It is difficult to imagine, as this treatise revolutionized our fundamental understanding of electric fields, magnetic fields, and light. The twenty original...
In a joint experimental and theoretical work performed at the Heidelberg Max Planck Institute for Nuclear Physics, an international team of physicists detected for the first time an orbital crossing in the highly charged ion Pr⁹⁺. Optical spectra were recorded employing an electron beam ion trap and analysed with the aid of atomic structure calculations. A proposed nHz-wide transition has been identified and its energy was determined with high precision. Theory predicts a very high sensitivity to new physics and extremely low susceptibility to external perturbations for this “clock line” making it a unique candidate for proposed precision studies.
Laser spectroscopy of neutral atoms and singly charged ions has reached astonishing precision by merit of a chain of technological advances during the past...
The ability to investigate the dynamics of single particle at the nano-scale and femtosecond level remained an unfathomed dream for years. It was not until the dawn of the 21st century that nanotechnology and femtoscience gradually merged together and the first ultrafast microscopy of individual quantum dots (QDs) and molecules was accomplished.
Ultrafast microscopy studies entirely rely on detecting nanoparticles or single molecules with luminescence techniques, which require efficient emitters to...
Graphene, a two-dimensional structure made of carbon, is a material with excellent mechanical, electronic and optical properties. However, it did not seem suitable for magnetic applications. Together with international partners, Empa researchers have now succeeded in synthesizing a unique nanographene predicted in the 1970s, which conclusively demonstrates that carbon in very specific forms has magnetic properties that could permit future spintronic applications. The results have just been published in the renowned journal Nature Nanotechnology.
Depending on the shape and orientation of their edges, graphene nanostructures (also known as nanographenes) can have very different properties – for example,...
Using a clever technique that causes unruly crystals of iron selenide to snap into alignment, Rice University physicists have drawn a detailed map that reveals...
03.12.2019 | Event News
15.11.2019 | Event News
15.11.2019 | Event News
12.12.2019 | Physics and Astronomy
12.12.2019 | Physics and Astronomy
12.12.2019 | Life Sciences