Comprehensive coverage

A new biomarker may improve the treatment of lung cancer patients

A study of human cancer tissues grown in mice has suggested that a large group of lung cancer patients may be successfully treated with a drug currently approved for other cancers

Human lung cancer cells with the L858R mutation in the EGFR gene. In blue - the cell nuclei. In red - a protein that appears in the cell fluid when EGFR receptors are active and push the cell into uncontrolled division. Courtesy of the Weizmann Institute
Human lung cancer cells with the L858R mutation in the EGFR gene. In blue - the cell nuclei. In red - a protein that appears in the cell fluid when EGFR receptors are active and push the cell into uncontrolled division. Courtesy of the Weizmann Institute

Smoking is the number one cause of lung cancer, but even those who have never smoked a cigarette may be at risk. More than one in ten cases of lung cancer is caused by mutations in the EGFR gene - and most of them are non-smokers. A new generation of drugs developed in the last decade offers effective and safe treatment for this subgroup of patients in the short term. However, within about a year, the tumors learn how to bypass the treatment and the cancer returns. In the study published today in the scientific journal Cell Report Medicine, Weizmann Institute of Science scientists present findings that may pave the way for treatment that will prevent the recurrence of the disease in a large group of lung cancer patients.

"We have found a potential biomarker that may change the way lung cancer patients are treated around the world," says Prof. Yosef Yordan, winner of the Israel Prize for Cancer Research and who led the new study. "Just as certain mutations in the BRCA gene predict how breast and ovarian cancer patients will respond to drugs, the new biomarker may also allow personalized treatment with improved chances of success for a distinct group of lung cancer patients."

Adapt the treatment to the mutation

EGFR - epidermal growth factor receptor - is a protein in the cell membrane, which receives messages from the environment that tell the cell to grow and divide. A malfunction in this mechanism, following mutations in the gene encoding the receptor, may cause cell division to go out of control and the development of a cancerous tumor. From a review of clinical studies carried out by Dr. Ilaria Morocco, until recently a post-doctoral researcher in Prof. Jordan's laboratory in the Department of Immunology and Biological Regeneration at the Institute, it emerged that although there are dozens of mutations in the EGFR gene, all patients diagnosed with mutations in this gene currently receive the same treatment regardless of their type of mutations. The drugs they receive are considered highly effective in the short term, but within a few months the cancer accumulates new mutations and other genetic changes that allow it to develop drug resistance.

In an attempt to examine the possibility of a personalized treatment that could replace the uniform treatment whose validity is limited in time, the researchers classified lung tumors according to the types of mutation in the EGFR gene and chose to focus on the L858R mutation, since it appears in approximately 40% of patients with mutations in this gene. This common mutation causes a change in the identity of one amino acid in a sequence of hundreds of amino acids that make up the receptor, but this change is enough to cause a serious disease.

"In cancer cells that carry this mutation, pairs of EGFR receptors found on the cell membrane must connect in order to transmit the division command to the cell nucleus," explains Prof. Jordan why they chose to focus on the L858R mutation. "We identified in the mice carrying the mutation that if the pairing between the receptors does not take place, this is like an electric short - the division command cannot pass to the cell nucleus and the cancerous growth is inhibited."

To prevent the receptors from connecting and leading to unbridled division, the researchers used the drug "Arbitox" based on an antibody that binds to the receptor and prevents its pairing with another receptor. "Arbitox" was developed based on the research of Prof. Jordan and the late Prof. Michael Sela and was approved in 2006 by the FDA for use in colon cancer tumors and head and neck cancer tumors.

In order to test the effectiveness of "Arbitox" in lung cancer tumors with the L858R mutation, the researchers used tumor samples that were removed from human patients and transplanted into mice as well as several other models. "Tumours with the L858R mutation that were treated with Arbitox shrank and we saw that there was no recurrence of the disease - not even in the medium or long term," Prof. Jordan describes the surprising findings. "The significance of this discovery is that it is possible that for a large group of lung cancer patients there is already a drug available today that may prevent the terrible scenario of the return of the cancerous tumors." 

But if "Arbitox" is so effective for treating lung cancer, why did previous attempts to treat patients with it fail or yield inconclusive results? "Since they were approved about a decade ago, EGFR inhibitors have become the first line of treatment for all patients with mutations in the EGFR gene, regardless of the identity and number of mutations in the gene," explains Prof. Jordan. "The drugs are indeed very effective in the short term, but they allow the cancer cells to develop new mutations that accelerate the recurrence of the disease. Our findings indicate that if 'Erbitox' is the first choice of treatment for patients with the specific mutation, the cancer is expected not to develop resistance in the first place."

The next step is a clinical trial that will test the effectiveness of Arbitox treatment in human cancer patients with the L858R mutation. The researchers hope that if the clinical trials reproduce the current findings, the transition from the laboratory to the clinic will be relatively quick, since "Arbitox" is already approved for the treatment of other types of cancer. "The L858R biomarker can help save lives," concludes Dr. Morocco, "there is real potential here for effective and personalized treatment in a large group of lung cancer patients."

Dr. Morocco is currently a researcher at the Catholic University of the Sacred Heart in Rome. Dr. Svando Giri, Dr. Arturo Simoni Niaves, Nitin Gupta, Anna Rodnicki, Dr. Arunchalam Sekar and Dr. Mosheet Lindzen from the Department of Immunology and Biological Regeneration at the Institute also participated in the study; Dr. Yuya Haga and Prof. Yasuo Tsutsumi from Osaka University in Japan; Dr. Donatella Romanello and Prof. Mattia Lauriola from the University of Bologna in Italy; Dr. Mary Zerbiv and Dr. Roni Oren from the Department of Veterinary Resources at the Institute; Dr. Damon Fard and Prof. And Luca Tamnione from the Catholic University of the Sacred Heart and the Agostino Gemelli University Polyclinic in Rome, Italy.

More of the topic in Hayadan:

Leave a Reply

Email will not be published. Required fields are marked *

This site uses Akismat to prevent spam messages. Click here to learn how your response data is processed.