Anew Israeli study could open the door to more efficient treatment of certain types of lung cancer, and the prevention of a relapse of illness.
Physicians routinely perform genetic testing on patients diagnosed with lung cancer. If certain genetic mutations are found, the patient may be treated with targeted therapy. These are drugs that target specific genes and proteins that help cancer cells survive and grow. Targeted therapy usually involves either monoclonal antibodies or small-molecule drugs, and has fewer side effects than chemotherapy.
Researchers at Prof. Yosef Yarden’s lab at the Weizmann Institute were puzzled by the fact that some lung cancer patients were suffering regression, with secondary gene mutations allowing tumors to develop resistance to the targeted therapy drugs.
They specifically reviewed cases of mutations in the EGFR (Epidermal Growth Factor Receptor) gene, responsible for making a receptor protein that spans the cell membrane, with one end of the protein remaining inside the cell and the other end projecting from the outer surface of the cell. One type of signal conveyed by the receptor is the message for the cell to proliferate.
Based on studies using mice, investigators identified a potential biomarker identifying which patients would benefit more long-term from a drug called cetuximab (brand name Erbitux). In research results published this month in the peer-reviewed Cell Reports Medicine journal, they demonstrated why the drug has a better chance of achieving remission in patients with a specific variant of the EGFR mutation.
Dr. Ilaria Marrocco, at the time of the study a postdoctoral student at Yarden’s lab, spotted the problem to be studied by reviewing the clinical literature. The lead investigator on the study, she is now a researcher in the Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore in Rome.
“We discovered that treatment with Erbitux only works when there is a specific EGFR mutation called L858R. This happens when a single amino acid, out of several hundred, is replaced with another one at point 858 in EGFR,” Marrocco told The Times of Israel.
Lung cancer is divided into two types: small cell (15% of cases) and non-small cell (85%). Up to 30% of non-small cell cases express an EGFR mutation. Among those, 40-45% involve L858R.
“We decided to focus on L858R because it accounts for almost half of the EGFR cases, and also because it is unique among the mutations in terms of how it functions,” Marrocco said.
In lung cancer tumors with other EGFR mutations, only one receptor on a tumor cell membrane is needed to send signals to the nucleus with the message to proliferate. However, with L858R, there must be a pair of receptors.
“The fact that in the case of L858R, the message to replicate is not sent unless there is a pair, was already known and published. We were able to show with a mouse model of lung cancer that the pairing’s signal could be short-circuited by treating the mice with Erbitux,” Marrocco said.
The drug was developed based on research by Yarden and the late Prof. Michael Sela. It has been approved by the FDA for the treatment of colon and head and neck cancers.
“After the treatment with Erbitux, the lung tumors of mice shrank and did not reappear, not even after a long while,” Yarden says. “These results indicate that, for the large number of human lung cancer patients who have the L858R mutation, a single drug might offer a path toward full recovery, without the devastating phenomenon of cancer relapse,” Yarden reported in a statement issued by the Weizmann Institute.
Marrocco said more lab studies need to be done, and that she is already in discussions with oncologists at a hospital in Rome to determine how human clinical trials might eventually be designed. She and Yarden are hopeful that the pathway to these trials will be eased by the fact that Erbitux has already been approved for treating other types of cancer.
by: Renee Ghert-Zand
published on The Times of Israel