Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

The mechanism of action of an antitumor drug used for the treatment of glioblastoma

03.05.2019

Glioblastoma is an incurable type of brain tumour that is frequently associated with mutations in the epidermal growth factor receptor (EGFR). The main EGFR mutation found in glioblastomas, called EGFRvIII, is treated with the antibody mAb806, a drug developed by the Ludwig Institute for Cancer Research (US) about 20 years ago, but whose mechanism of action was unknown. In collaboration with the University of Stockholm (Sweden) and the University of California San Diego (USA), researchers at the Institute for Research in Biomedicine (IRB Barcelona) have unravelled how this antibody acts on mutated EGFR, thus dramatically extending its application to virtually any glioblastoma mutations.

Published in the journal PNAS, the study paves the way for new treatments for cancer. The results of the work indicate that, in contrast to what was previously believed, mAb806 could be used to treat many tumours that carry EGFR mutations and not only for a specific mutation.


This is the structure of EGFR. Purple indicates the region recognised by mAB806.

Credit: Laura Orellana

Furthermore, the scientists have demonstrated that even when EGFR is not mutated, it can be treated in order to make it susceptible to mAb806 therapy.

"This finding lays the rational basis for anti-EGFR combination treatments with antibodies and kinase inhibitors, instead of "blind testing" them, as has been done until now," says Modesto Orozco, head of the Molecular Modelling and Bioinformatics Lab at IRB Barcelona and senior professor of the Faculty of Chemistry at the University of Barcelona.

More than 100 mutations in EGFR have been described to give rise to glioblastoma. By means of computational simulation, Laura Orellana, first author of the study who began this project during her PhD at IRB Barcelona and is now a researcher at Stockholm University, discovered that the mutations studied induced a similar change in the shape of the receptor.

"Surprisingly, this change in EGFR matches the shape recognised by mAb806, but this hadn't previously been observed experimentally," she comments.

Previous studies had reported that mAb806 recognises a region of EGFR that is normally hidden. In certain tumours carrying EGFRvIII, half of the receptor has been removed, so that this region becomes accessible, thereby allowing the therapeutic use of the antibody.

The researchers have now demonstrated that many different mutations on EGFR change the shape of the receptor, allowing mAb806 to detect this "hidden" region.

These changes in the shape of EGFR affect its activation. While analysing computational simulations of EGFR, Orellana discovered that while a part of the receptor is "eliminated in EGFRvIII, in other mutants this same part is "displaced", with the same objective of activating the receptor.

"This surprising finding provides a rational basis to explain why distinct mutations in glioblastoma respond to drugs in a similar manner," explains Orellana. "Mutations that are seemingly different are in fact equivalent and have the same effect on the receptor, driving the formation of a tumour".

In collaboration with the Ludwig Institute for Cancer Research and the University of California San Diego, the researchers validated this computational hypothesis using cell and animal models, which confirmed the therapeutic potential of mAb806a.

"Given the numerous clinical assays underway with mAb806 worldwide, the translation of these results into clinical practice will be much faster than normal, and treatment with this antibody is expected to be suitable for many types of tumour that carry similar mutations, such as tumours found in the colon, breast and skin," says Orozco.

###

The study is a collaboration between IRB Barcelona, the Royal Institute of Technology (KTH) of Stockholm, the University of Stockholm, the Ludwig Institute for Cancer Research, the University of California San Diego, the Barcelona Supercomputing Center, the University of Lisbon and the Centre de Biochimie Structurale (CNRS).

The study was funded by the Ministry of Science, Innovation and Universities, ICREA, the Catalan Government, the European Research Council, Vetenskapsrådet and the Swedish e-Science Research Center (E.L.)

Reference article:

Laura Orellana, Amy H. Thorne, Rafael Lema, Johan Gustavsson, Alison D. Parisian, Adam Hospital, Tiago N. Cordeiro, Pau Bernadó, Andrew M. Scott, Isabelle Brun-Heath, Erik Lindahl, Webster K. Cavenee, Frank Furnari and Modesto Orozco.

Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope.

PNAS (2019) doi: 10.1073/pnas.1821442116.

Media Contact

Communications IRB Barcelona
communications@irbbarcelona.org

http://www.irbbarcelona.org 

Communications IRB Barcelona | EurekAlert!
Further information:
https://www.irbbarcelona.org/en/news/researchers-discover-the-mechanism-of-action-of-an-antitumour-drug-used-for-the-treatment-of
http://dx.doi.org/10.1073/pnas.1821442116

Further reports about: CANCER EGFRvIII IRB PNAS antitumor drug computational simulations mutations receptor tumours

More articles from Life Sciences:

nachricht A human liver cell atlas
15.07.2019 | Max Planck Institute of Immunobiology and Epigenetics

nachricht Researchers reveal mechanisms for regulating temperature sensitivity of soil organic matter decompos
15.07.2019 | Chinese Academy of Sciences Headquarters

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Artificial neural network resolves puzzles from condensed matter physics: Which is the perfect quantum theory?

For some phenomena in quantum many-body physics several competing theories exist. But which of them describes a quantum phenomenon best? A team of researchers from the Technical University of Munich (TUM) and Harvard University in the United States has now successfully deployed artificial neural networks for image analysis of quantum systems.

Is that a dog or a cat? Such a classification is a prime example of machine learning: artificial neural networks can be trained to analyze images by looking...

Im Focus: Extremely hard yet metallically conductive: Bayreuth researchers develop novel material with high-tech prospects

An international research group led by scientists from the University of Bayreuth has produced a previously unknown material: Rhenium nitride pernitride. Thanks to combining properties that were previously considered incompatible, it looks set to become highly attractive for technological applications. Indeed, it is a super-hard metallic conductor that can withstand extremely high pressures like a diamond. A process now developed in Bayreuth opens up the possibility of producing rhenium nitride pernitride and other technologically interesting materials in sufficiently large quantity for their properties characterisation. The new findings are presented in "Nature Communications".

The possibility of finding a compound that was metallically conductive, super-hard, and ultra-incompressible was long considered unlikely in science. It was...

Im Focus: Modelling leads to the optimum size for platinum fuel cell catalysts: Activity of fuel cell catalysts doubled

An interdisciplinary research team at the Technical University of Munich (TUM) has built platinum nanoparticles for catalysis in fuel cells: The new size-optimized catalysts are twice as good as the best process commercially available today.

Fuel cells may well replace batteries as the power source for electric cars. They consume hydrogen, a gas which could be produced for example using surplus...

Im Focus: The secret of mushroom colors

Mushrooms: Darker fruiting bodies in cold climates

The fly agaric with its red hat is perhaps the most evocative of the diverse and variously colored mushroom species. Hitherto, the purpose of these colors was...

Im Focus: First results of the new Alphatrap experiment

Physicists at the Max Planck Institute for Nuclear Physics in Heidelberg report the first result of the new Alphatrap experiment. They measured the bound-electron g-factor of highly charged (boron-like) argon ions with unprecedented precision of 9 digits. In comparison with a new highly accurate quantum electrodynamic calculation they found an excellent agreement on a level of 7 digits. This paves the way for sensitive tests of QED in strong fields like precision measurements of the fine structure constant α as well as the detection of possible signatures of new physics. [Physical Review Letters, 27 June 2019]

Quantum electrodynamics (QED) describes the interaction of charged particles with electromagnetic fields and is the most precisely tested physical theory. It...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on UV LED Technologies & Applications – ICULTA 2020 | Call for Abstracts

24.06.2019 | Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

 
Latest News

A human liver cell atlas

15.07.2019 | Life Sciences

No more trial-and-error when choosing an electrolyte for metal-air batteries

15.07.2019 | Power and Electrical Engineering

Possibilities of the biosimilar principle of learning are shown for a memristor-based neural network

15.07.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>