Posted on 08/04/2021 12:06:51 PM PDT by Red Badger
A protein in tumor cells could be targeted to treat some types of aggressive cancer including brain, blood, skin, and kidney, new research has shown.
The scientists, from the Wellcome Sanger Institute, University of Cambridge and Harvard University, have identified a protein that plays a key role in transforming normal tissue into cancer, as a possible target for drug development. Inhibiting this protein effectively destroys cancer cells in laboratory models, including in cell lines and mice, while leaving healthy cells unharmed.
The research, published today in Molecular Cell, provides strong evidence that developing drugs that block the RNA-modifying protein known as METTL1 could give people with aggressive brain, blood, skin, and kidney cancers new treatment options.
RNA-modifying proteins, in particular the METTL family, are involved heavily in cell replication. These proteins have been found in higher levels in certain cancer cells, including some brain, blood, pancreatic, and skin cancers, and are associated with poorer outcomes.
Previously, Dr. Tzelepis, along with his team at the University of Cambridge, and their 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 that research, researchers at the Wellcome Sanger Institute, University of Cambridge, and Harvard University have now found that mutations in the METTL1 gene which lead to higher levels of the METTL1 protein, cause the cells to replicate faster and transform into a cancerous state, producing highly aggressive tumors.
When the team inhibited the METTL1 protein by knocking out the gene, it stopped cancer cell growth while leaving the normal healthy cells unharmed, in both laboratory and mice models, suggesting it would be a good target for cancer treatments.
Recently, the team also developed a small-molecule inhibitor for a similar protein, METTL3, to help treat acute myeloid leukemia, which will be entering clinical trials in 2022. It is hoped that this new research provides the evidence needed to start to develop a similar drug that targets METTL1, which could be used to treat a wider range of 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 poorer outcomes, it could also be used as a biomarker to inform treatment plans and identify those who would benefit if a drug was developed, to ensure clinical trials are as streamlined and personalized as possible.
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."
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. 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 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."
Explore further
Eliminating RNA-binding protein improves survival in aggressive leukemia
More information: METTL1-mediated m7G modification of Arg-TCT tRNAÂ drives oncogenic transformation, Molecular Cell (2021). DOI: 10.1016/j.molcel.2021.06.031
Tian, Q.H., Zhang, M.F., Zeng, J.S., Luo, R.G., Wen, Y., Chen, J., Gan, L.G., and Xiong, J.P. (2019). METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN. J Mol Med (Berl) 97, 1535-1545. DOI: 10.1007/s00109-019-01830-9
Tzelepis K, Koike-Yusa H, De Braekeleer E, Li Y, Metzakopian E, Dovey OM, Mupo A, Grinkevich V, Li M, Mazan M et al.(2016) A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia. Cell reports. 17;4;1193-1205.
Barbieri I, Tzelepis K, Pandolfini L, Kouzarides T, et al. (2017) Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature. 27;552(7683):126-131. DOI: 10.1038/nature24678
Journal information: Molecular Cell , Cell Reports , Nature
Provided by Wellcome Trust Sanger Institute
Bkmk
Very interesting, a potential target for a magic bullet.
**
This is the latest and most promising "strategy" for fighting cancer, namely to identify specific targets in the biochemistry of cancer cells and to design chemical monkey wrenches to throw at those targets. In the medical literature I'm reading concerning my own rare cancer, these new drugs are usually called "targeted therapies" or "target drugs" to distinguish them from the much older "chemotherapies" which have a much broader range of cells which they attack - not just rapidly dividing cancer cells, but other rapidly dividing cells, such as blood components, hair, some gastrointestinal linings, mucous membranes, etc.
If you want to learn about another kind of spookey, science-fictiony sort of strategy for fighting cancer, look up the videos on You tube which explain CAR-T cell therapy. This is likely what I will use to fight a very rare cancer with lousy prognosis (overall survival is 10 months, max; half die by five months).
This is very Wellcome news.
(I’ll show myself out).
Good luck with your treatment, Brandybux. Keep us posted.
Best of luck to you!
wow- sorry to hear that- May God help you endure it- and if it be His will to cure you of it using the more targeted treatment- -
forgot to add- let’s pray that it is His will to give remission-
The Israelis have been chasing this down in recent years.
They noticed that the moment a cancer cell divides, it grabs a protein and uses it in its replication. By introducing a different protein, researchers get the cancer cell to grab it and stop dividing.
They have been able to eliminate pancreatic adenocarcinoma, one of the deadliest cancers, in animal testing.
Prayers up for you - my older Brother had this sort of therapy to treat inoperable esophageal cancer.
The Cancer Treatment Center of America told him there was nothing that could be done and he had a year at most to live.
He’s currently in remission - last PET scan found no tumor.
Thank you for your well-wishes. I am convinced that "good luck" is the unbeliever's term of art for what I would call the good will of my Father in heaven, the Father of my Lord Jesus Christ.
Now, this is not inconsistent with His using any agents He pleases to effect the good will He shows us sinners. Agents, for example, as my oncologist.
As for answering your query, here's the very short report:
1. I am presently undergoing "conventional" chemotherapy (losing hair, losing a bear I've had for over 50 years, etc.) to "clear out the junk in your torsod" (my oncologist's way of putting things).
2. I'm simultaneously taking one of those targeted drugs.
hA PET scan last week showed almost complete remission. I will continue both strategies for another nine weeks, then a subsequent PET scan to verify what we hope will be a complete remission, knowing (of course) that this simply means no cancer is detectable. We can bet the bank that it's still there, lurking somewhere, waiting to return in a far more drug-resistant form.
Then we hit it with CAR-T. This has been tried with five others aross the country, and none show any cancer for many, many months thereafter. They appear to be cured, to judge by this cancer's behavior with conventional therapies, including stem-cell transplants.
I've had a generous and blessed life - wonderful wife of 40 years, four lovely daughters, two upstanding and productive sons-in-law, six (so far) delightful grandchildren. I'm rich, rich, rich in what really matters. I have no fear of death, but would prefer to see my wife safely in heaven before me.
So, really, I can't lose, no matter what happens. I am very interested in this research into novel and promisng cancer therapies, as they seem to be advancing most rapidly in immune-system cancers. It would be fun to show my grand kids a case-study about their grandfather, reporting a cure of CLL with Richter transformation through some cutting-edge novel therapies! My name wouldn't be in the article, of course. But, I could tell them "That's your Poppa he's writing about!" That would be thick icing on the cake.
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