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
Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania
The strange double life of Dab2
10.01.2017 | University of Miami Miller School of Medicine
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Materials Sciences
17.01.2017 | Architecture and Construction