Discovery of a potential therapeutic target for several aggressive cancers
A protein found in tumor cells could be targeted to treat certain types of aggressive cancer, including the brain, blood, skin and kidneys, new research shows.
Scientists at the Wellcome Sanger Institute, Cambridge University and Harvard University have identified a protein that plays a key role in turning normal tissue into cancer, as a possible target for drug development. Inhibition of this protein effectively destroys cancer cells in laboratory models, including cell lines and mice, while leaving healthy cells unharmed.
The research, published today (August 4, 2021) in Molecular cell, provides strong evidence that the development of drugs that block the RNA-modifying protein known as METTL1 may offer people with aggressive cancers of the brain, blood, skin and kidneys new options for treatment.
RNA modifying proteins, in particular the METTL family, are strongly involved in cell replication. These proteins have been found at higher levels in certain cancer cells, including certain cancers of the brain, blood, pancreas and skin, and are associated with poorer results *.
Previously, Dr Tzelepis, along with his team at Cambridge University and collaborators at the Wellcome Sanger Institute, used CRISPR-Cas9 gene editing technology to screen cancer cells for vulnerable points. The researchers identified the METTL1 gene – a gene that produces the RNA-modifying METTL1 protein – as a target for drug development **.
In a new study that builds on this research, researchers at the Wellcome Sanger Institute, the University of Cambridge and Harvard University have now found that mutations in the METTL1 gene that leads to higher levels of the METTL1 protein, accelerates cell replication and turns into a cancerous state, producing very aggressive tumors.
When the team inhibited the METTL1 protein by removing the gene, they stopped the growth of cancer cells while leaving normal healthy cells unharmed, both in laboratory and mouse models, suggesting it would be a good target. for cancer treatments.
Recently, the team has also developed a small molecule inhibitor for a similar protein, METTL3, to help treat acute myeloid leukemia, which will enter clinical trials in 2022. It is hoped that this new research will provide the evidence needed to start developing a similar drug targeting METTL1, which could be used to treat a wider range. off aggressive cancers if they have a mutation in the METTL1 gene or high levels of its protein.
As the METTL1 protein is elevated in cancer cells with lower results, it could also be used as a biomarker to inform treatment plans and identify those who would benefit from drug development, to ensure that clinical trials are as well. streamlined and personalized as possible.
Professor Richard Gregory, co-lead author and senior researcher at Boston Children’s Hospital and Harvard Medical School in Boston, said: There is still a lot to discover. This research deeply sheds light on the role of the METTL1 protein in the development of cancer and proves that mutations in this gene can make a cell cancerous. The more we understand the genetic basis of cancer and how we can fight it, the more we can create targeted, life-changing treatments. “
Dr Esteban Orellana, lead author and researcher at Boston Children’s Hospital, said: “Our research provides incredibly strong evidence that targeting the RNA-modifying protein, METTL1, is an effective treatment for certain cancers, helping to kill cancer cells while leaving other cells in the body intact. This is important because it could mean that there will be fewer unpleasant side effects from a potential new treatment. The next step in this research is to try to develop a small molecule inhibitor to block METTL1 to see if our encouraging results can be clinically translated. “
Dr Konstantinos Tzelepis, co-lead author, group leader at the University of Cambridge and visiting scientist at the Wellcome Sanger Institute, said: “This study provides another great example of what is possible with the use of CRISPR technologies. and how we can take and prioritize precise genetic information and turn it into something of potential clinical benefit. Targeting RNA-modifying proteins can effectively destroy cancer cells and we hope this research will provide the evidence necessary for the development of drugs targeting METTL1, potentially providing new therapy against aggressive cancers with a clear and unmet therapeutic need.
Reference: Orellana EA, Liu Q, Yankova E, et al. METTL1-mediated
The m7G modification of Arg-TCT tRNA results in oncogenic transformation. Molecular
Cell. 2021. doi: 10.1016 / j.molcel.2021.06.031
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