Biologists and oncologists have long understood that a protein called the epidermal growth factor receptor or EGFR is altered in at least 50 percent of patients with glioblastoma. Yet patients with glioblastoma either have upfront resistance or quickly develop resistance to inhibitors aimed at stopping the protein's function, suggesting that there is another signalling pathway at play.
Researchers from the Ludwig Institute for Cancer Research, the University of California, San Diego (UCSD) and Los Angeles (UCLA) and the University of São Paulo, Brazil published their findings on a mechanism that defines these types of resistance in the August 13 online issue of Proceedings of the National Academy of Sciences.
Previous research suggested that PTEN, a tumor suppressor gene, may be turned off in some cancer patients, disabling its function and potentially causing the resistance to EGFR inhibitors. "We asked ourselves, how is PTEN being modified? What is altering its function?," said Frank Furnari, PhD, corresponding author and Ludwig senior investigator based at UCSD.
The researchers focused on one type of modification called phosphorylation, the process by which some proteins are turned on and off. They mapped the sites where PTEN was changed or phosphorylated and subsequently developed an antibody that would recognize the PTEN protein when it was phosphorylated.
The team then put the antibody to the test. Together with Suely Marie, MD, at the University of São Paulo, they first evaluated a large series of clinical samples from patients with glioblastoma and found that the presence of phosphorylation was associated with shortened survival. Then with Paul Mischel, MD, at UCLA, they examined samples from a completely different series of patients who were EGFR positive and did not respond to EGFR-inhibitor treatment. The results confirmed that patients with modified PTEN had resistance to EGFR inhibitors.
"We think this modification of PTEN may become a useful marker to determine if a patient will respond or not to a growth factor receptor inhibitor," added Furnari. "If you can prevent phosphorylation, our studies showed that you have created a scenario where EGFR inhibitors will work better."
The team identified two enzymes responsible for turning off the brakes of PTEN – the fibroblast growth receptor and SRC family kinases. By understanding how these enzymes disable the suppressor function of the gene, scientists may be able to target different molecules that can intervene to stop resistance.
"The more we understand, the better we can conceive of ways to restore PTEN function in tumor cells and stop resistance to EGFR inhibitors in patients with glioblastoma," said lead author, Tim Fenton, PhD, who conducted this research while at the Ludwig Institute at UCSD and is currently at the University College London Cancer Institute.
According to Paul Mischel, who has since moved from UCLA to become a Ludwig member based at UCSD, "The study outcomes provide a potentially clinically targetable pathway. The findings enable us to move forward to identify and develop small molecule inhibitors for eventual use in combination with EGFR inhibitors for the treatment of glioblastoma and other cancers."
Funding for this research came from the Ludwig Institute for Cancer Research, the Goldhirsh Foundation, NIH Grants P01-CA95616 and P50-CA097257 and FAPESP grant 04/12433-6.
About The Ludwig Institute for Cancer Research
LICR is an international non-profit organization committed to improving the understanding and control of cancer through integrated laboratory and clinical discovery. Leveraging its worldwide network of investigators and the ability to sponsor and conduct its own clinical trials, the Institute is actively engaged in translating its discoveries into applications for patient benefit. Since its establishment in 1971, the Institute has expended more than $1.5 billion on cancer research.
Rachel Steinhardt | EurekAlert!
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
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...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Power and Electrical Engineering
16.01.2017 | Information Technology
16.01.2017 | Power and Electrical Engineering