New therapeutic target discovered for a number of aggressive cancers


Date:
August 4, 2021
Source:
Wellcome Trust Sanger Institute
Summary:
An RNA-modifying protein elevated in some aggressive cancers has
been shown to be a promising target for new drug development.



FULL STORY ==========================================================================
A protein in tumour 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 (4 August 2021) 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 METTL1gene -- 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 tumours.



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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 leukaemia, 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 personalised 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 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." * 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 ========================================================================== Story Source: Materials provided by Wellcome_Trust_Sanger_Institute. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Esteban A.Orellana et al. METTL1-mediated m7G modification of
Arg-TCT
tRNA drives oncogenic transformation Author links open overlay
panel.

Molecular Cell, 2021 DOI: 10.1016/j.molcel.2021.06.031 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210804123449.htm

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