Credit: National Cancer Institute
A new study published by CSCI scientists today (28 October) in Nature has led to the potential development of a new type of therapy that could target aggressive cancers by blocking a process that cancer cells rely on to survive.
The team, led by Professor Konstantinos Tzelepis, Group Leader at the Cambridge Stem Cell Institute (CSCI) and University of Cambridge, focused on a protein called METTL1, which plays an important role in regulating RNA, the molecules that carry genetic instructions and help cells produce the proteins they need. By modifying RNA, METTL1 can influence how efficiently certain proteins are made, affecting processes such as cell growth and survival.
In cancer, however, the METTL1 pathway can alter how proteins are produced. Cancer cells need to produce large amounts of protein to support their rapid growth and survival, and increased METTL1 activity has been linked to the development of several aggressive cancers such as Acute Myeloid Leukaemia, melanoma, glioblastoma, and liver and lung cancers.
Prof Tzelepis describes the process of the METTL1 pathway as a "molecular tattoo". Just as a tattoo leaves a recognisable mark, METTL1 adds chemical tags to RNA that create a distinctive molecular signature that cancers take advantage of.
Researchers can detect and study these signatures to identify shared vulnerabilities and develop treatments that target a fundamental process cancer cells depend on.
This is exactly what Prof Tzelepis, Dr Eliza Yankova (a Leukaemia UK John Goldman Fellow at CSCI and joint co-author of the paper), and collaborators at Storm Therapeutics demonstrated in their study. Through the screening of approximately 250,000 potential compounds, they identified STM9005 as a highly selective inhibitor that could block METTL1 activity.
Extensive testing confirmed that the compound effectively targets METTL1, blocking cancer cell growth and reducing the ability of cancer cells to survive and spread.
Prof Tzelepis says, “By understanding this signature, we can begin to uncover vulnerabilities that cancer cells depend on for survival and develop therapies that target these underlying mechanisms. We are delighted to have developed the first highly selective inhibitor of METTL1. Our findings provide strong evidence that this approach has the potential to be developed further as a treatment strategy for multiple aggressive cancers."
Dr Yankova says, “Many people with aggressive cancers face treatments that are tough on the body, and we urgently need gentler options. Our results show that blocking METTL1 can slow tumour growth and extend survival in preclinical models, and although there is still a long way to go before this could reach patients, it is a new therapeutic approach for a range of cancers”.
That METTL1 inhibitors could represent an entirely new class of therapies could be significant for patients living with cancer diagnoses, and especially Acute Myeloid Leukaemia (AML), which has one of the worst survival rates of any cancer. These findings provide strong evidence that targeting the METTL1 pathway could be a viable therapeutic strategy for AML and other cancers, offering hope of treatment for even some of the most aggressive forms of cancer.
This work was mainly supported by Wellcome, MRC, Leukaemia UK and CRUK.