Novel drug type for blood cancer entering clinical trials 

First drug to target a specific RNA-modifying protein will start clinical trials in 2022 against acute myeloid leukaemia 

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A novel drug for the blood cancer, acute myeloid leukaemia will enter clinical trials next year, making it one of the first bench-to-clinic cancer drugs to come from using CRISPR technology.

The new drug, which can target a protein needed for blood cancer cells to survive, has been developed to treat patients with acute myeloid leukaemia, including children. The drug is the result of a research collaboration between scientists from the Wellcome Sanger Institute, University of Cambridge, and STORM Therapeutics.

The research, published today (26 April 2021) in Nature, shows that inhibiting the protein, METTL3 effectively destroys blood cancer cells in laboratory models, including in cell lines and mice. The findings provide the evidence needed for this type of drug to go forward into clinic trials for acute myeloid leukaemia, and paves the way for similar anti-cancer treatments to be developed.

Acute myeloid leukaemia (AML) is an aggressive blood cancer that affects people of all ages, often requiring months of intensive chemotherapy and prolonged hospital admissions. It develops in cells in the bone marrow crowding out the healthy cells, in turn leading to life-threatening infections and bleeding. Mainstream AML treatments have remained unchanged for decades* and fewer than one in three people survive the cancer**.

Previously, using CRISPR-Cas9 gene-editing technology to screen cancer cells for vulnerable points, the team identified the METTL3 gene – a gene that produces the RNA-modifying METTL3 protein – as a target for drug development***.

While the team identified multiple RNA-modifying genes that could be potentially targeted, they found that METTL3 was essential for the creation and survival of AML cells, but it was not required for healthy blood cells, making it a good potential drug target.

Working with STORM therapeutics, researchers developed and characterised a drug (STM2457) that inhibits part of the METTL3 protein, stopping it from carrying out its function in AML cells, which will now enter the clinic for trials in 2022. This research provides proof that METTL3 inhibitors show promise in treating AML. It also shows that targeting RNA-modifying proteins could be a new therapeutic avenue against aggressive malignancies.

“Proteins are essential for our bodies to function and are produced by a process that involves translating our DNA into RNA using enzymes. Sometimes, this process can go awry with potentially devastating consequences for human health. Until now, no one has targeted this essential process as a way of fighting cancer. This is the beginning of a new era for cancer therapeutics.”

Professor Tony Kouzarides, co-lead author Professor of Cancer Biology at the University of Cambridge and a senior group leader at the Gurdon Institute

In order to treat AML, chemotherapy removes the majority of blood stem cells – both healthy and cancerous – to try and reset the body. Sometimes there are a small amount of blood stem cells that are left behind, which go on to become resistant to treatment and lead to the return of AML. Inhibition of METTL3 by this drug could be effective in these cells, when used alongside chemotherapy or any other mainstream treatment, as it effects those drug-persistent cancer stem cells, potentially leaving the patient cancer free.

“I am delighted to see the publication of our ground-breaking research on STM2457 in a world leading journal. We are excited to be leading the field having selected STC-15, STORM’s first-in-class clinical candidate targeting METTL3 for development towards first in human clinical studies in 2022, addressing AML patients refractory to chemotherapy treatment with limited other options in addition to exploring combinations with standard of care.”

Keith Blundy, CEO of STORM Therapeutics

Initially, the clinical trials will focus on adults with advanced AML, however if this is shown to be effective and safe, the drug also holds potential in treating children with AML. In children, AML is treated with high doses of chemotherapy, and this new avenue may help improve their prognosis dramatically.

“This study is a great example of what is possible with the use of CRISPR technologies and the systematic investigation of novel cancer vulnerabilities. We started this effort six years ago at the Sanger Institute, and this is one of the first examples that CRISPR research has led to the development and characterisation of a new drug to help treat cancer. We believe that this approach – of targeting RNA enzymes – could be used to treat a wide range of cancers, other than AML, potentially offering us a new weapon in our arsenal against these terrible diseases”

Dr Konstantinos Tzelepis, senior author, group leader at the University of Cambridge, Leukaemia UK Fellow, and visiting scientist at the Wellcome Sanger Institute

More information

* J.S. Evans, E.A. Musser, G.D. Mengel, K.R. Forsblad, J.H. Hunter. (1961) Antitumor activity of 1-beta-D-arainofuranosylcytosine hydrochloride. Proc. Soc. Exp. Biol. Med., 106, pp. 350-353

** F. Ferrara, C.A. Schiffer.(2013) Acute myeloid leukaemia in adults. Lancet, 381, pp. 484-495

*** 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


Eliza Yankova, Wesley Blackaby, et al. (2021) Small molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature. DOI: 10.1038/s41586-021-03536-w


This project was funded by Cancer Research UK, Kay Kendall Leukaemia Fund, Leukaemia UK and Wellcome.