The mechanism of action of an antitumor drug used for the treatment of glioblastoma
Glioblastoma is an incurable type of cerebral tumor that is frequently associated with mutations in the epidermal growth factor (EGFR) receptor. The main EGFR mutation found in glioblastomas, called EGFRvIII, is treated with the mAb806 antibody, 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 in San Diego (USA), researchers from the Institute for biomedicine research (IRB Barcelona) have unravelled the way this antibody acts on the transferred EGFR, so in a way to extend its application to practically all mutations of glioblastoma.
Published in the PNAS magazine, the study opens the way for new treatments for cancer. The results of the work indicate that, contrary to what was previously believed, mAb806 could be used to treat many tumors that carry EGFR mutations and not just for a specific mutation.
In addition, scientists have shown that even when EGFR is not mutated, it can be treated to make it susceptible to mAb806 therapy. This finding establishes the rational basis for anti-EGFR combination treatments with antibodies and kinase inhibitors, instead of "the blind tests " them, as has been done so far, "says Modesto Orog, head of the laboratory of molecular modeling and bioinformatics at IRB Barcelona and senior Professor of the Faculty of chemistry of the University of Barcelona.
Over 100 mutations of EGFR have been described to give rise to glioblastoma. Using computational simulation, Laura Orellana, the first author of the study that started this project during her PhD at the IRB in Barcelona and is now a researcher at the University of Stockholm, discovered that the mutations studied induce a similar change in the shape of the receiver. "Surprisingly, this change in EGFR corresponds to the form recognized by mAb806, but this had not been previously observed experimentally," she commented.
Previous studies had reported that mAb806 recognized an EGFR region that is normally hidden. In some tumors carrying EGFRvIII, half of the receptor has been removed, so that this region becomes accessible, thus allowing the therapeutic use of the antibody. Researchers have now shown that many different mutations on EGFR change the shape of the receiver, which allows mAb806 to detect this region "hidden ".
These changes in the form of EGFR affect its activation. While analyzing the computational simulations of EGFR, Orellana discovered that if a part of the receiver is "eliminated in EGFRvIII, in other mutants, this same part is " moved, "with the same purpose of activating the receiver.
"This surprising finding provides a rational basis for explaining why distinct mutations in glioblastoma react to the drug in a similar way," explains Orellana. "Mutations that are apparently different are actually equivalent and have the same effect on the receptor, leading to the formation of a tumor. "
In collaboration with the Ludwig Institute for cancer research and the University of California in San Diego, researchers validated this hypothesis of calculation using cell and animal models, confirming the therapeutic potential of mAb806a.
"Given the numerous clinical trials underway with mAb806 worldwide, translating these results into clinical practice will be much faster than normal, and treatment with this antibody should be suitable for many types of tumors that are wearing like tumors found in the colon, breast and skin, "says Orob.
