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Hopes of target for new drugs to fight aggressive cancers after protein discovery by Cambridge, Sanger Institute and Harvard scientists




Researchers have identified a protein that plays a key role in transforming normal tissue into cancer in a discovery that raises hopes of a target for new drugs.

The scientists at the Wellcome Sanger Institute, University of Cambridge and Harvard University say there is “incredibly strong evidence” that this approach could help those with aggressive brain, blood, skin and kidney cancers.

Understanding the genetic basis of cancers can help guide new treatments
Understanding the genetic basis of cancers can help guide new treatments

Inhibiting the protein effectively destroys cells in laboratory models - both cell lines and mice - but leaves healthy cells unharmed, the researchers reported in the journal Molecular Cell.

Known as METTL1, it is an RNA-modifying protein. This type of protein, and particularly those in the METTL family, are heavily involved in cell replication. They have been found in higher levels in certain cancer cells, including some brain, blood, pancreatic and skin cancers, and have been associated with poorer outcomes for patients.

Professor Richard Gregory, co-lead author and principle Investigator at Boston Children’s Hospital and Harvard Medical School, Boston, said: “Cancer cells benefit from an unregulated cell cycle, leading to increased replication, and while some of the reasons behind this are known, there is still a lot to discover.

“This research illuminates deeply the role of the METTL1 protein in cancer development and proves that mutations in this gene can cause a cell to become cancerous. The more we understand about the genetic basis of cancer and how we can combat this, the more life changing targeted treatments we can create.”

Previously, Dr Konstantinos Tzelepis and his team at the University of Cambridge, along with their collaborators at the Sanger Institute, used CRISPR-Cas9 gene-editing technology to screen cancer cells for vulnerable points, identifying the METTL1 gene, which produces the protein, as a potential target for drug development.

The new research shows mutations in the METTL1 gene lead to higher levels of the METTL1 protein, causing the cells to replicate faster and transform into a cancerous state, which produces highly aggressive tumours.

The researchers inhibited the METTL1 protein by knocking out the gene and found it stopped cancer cell growth without harming normal healthy cells.

A small-molecule inhibitor for a similar protein, METTL3, has already been developed by the team to help treat acute myeloid leukaemia and is due to enter clinical trials in 2022.

The latest study provides evidence to support the development of a similar drug that targets METTL1, which could help treat a wider range of aggressive cancers with the METTL1 gene mutation or high levels of its protein.

And since the METTL1 protein is elevated in cancer cells with poorer outcomes, it could also be used as a biomarker, informing patients’ treatment plans and identifying those who could benefit should a drug be successfully developed. This approach could also help ensure clinical trials are personalised.

Dr Esteban Orellana, first author and Research Fellow at Boston Children’s Hospital, said: “Our research gives incredibly strong evidence that targeting the RNA modifying protein, METTL1, is an effective treatment against certain cancers, helping to kill cancer cells while leaving the other cells in the body untouched.

“This is important as it could mean that there will be fewer unpleasant side effects of a potential new treatment. The next step for this research is to try and develop a small molecule inhibitor to block METTL1 to see if our encouraging results can be translated across to the clinic.”

Dr 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 prioritise precise genetic information and turn it into something of potential clinical benefit. Targeting RNA-modifying proteins can effectively destroy cancer cells and we hope that this research will provide the evidence necessary for drugs to be developed that target METTL1, potentially providing a new therapy against aggressive cancers with clear and unmet therapeutic need.”

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