“Scientists have found a way to disarm a protein thought to play a key role in leukaemia and other cancers,” the BBC has reported. It said that the protein in question, called Notch, is often found to be damaged or mutated in...
“Scientists have found a way to disarm a protein thought to play a key role in leukaemia and other cancers,” the BBC has reported. It said that the protein in question, called Notch, is often damaged or mutated in patients with a certain form of leukaemia.
The researchers used an experimental technique called hydrocarbon stapling. This uses a chemical ‘scaffold’ to mould short sections of protein (called peptides) into specific three-dimensional shapes. The researchers hoped that these 'stapled peptides' would interact with the Notch protein and block its actions. The researchers found that one of their peptides was able to stop Notch from working and to reduce the growth of leukaemia cells in mice.
This research has identified a way to target the Notch protein, which has previously been an elusive target. The technique may lead to the development of new drugs to treat this type of leukaemia (called T-ALL), and to potential ways of using stapled peptides in other areas of research.
Where did the story come from?
Dr Raymond Moellering and colleagues from Harvard University carried out this research. The study was funded by several organisations, including the Leukaemia & Lymphoma Society and the National Institutes of Health in the US.
One of the researchers declared that they were a paid consultant and shareholder of Aileron Therapeutics, a company which has been granted a license to develop stapled peptide technology by Harvard University and the Dana Farber Cancer Institute. The study was published in the peer-reviewed journal Nature.
The BBC has covered this complex study in a balanced way.
What kind of research was this?
This was a laboratory study that included both biochemical and animal experiments. The researchers wanted to see if they could develop a method to block the action of transcription factors (a type of protein) in cells. Transcription factors switch on genes and, as such, they control the processes that occur within cells. While transcription factors play a role in normal cell function, they are also involved in the development of cancer. This means that they may be a good target for new cancer drugs, but their chemical characteristics have so far made it difficult to design drugs that block their function.
This study describes the early development of a new type of molecule that could be used in future drugs. This work will be followed by further research in animals to investigate the molecule’s effectiveness and safety. If this research proves promising, it may be followed by research in humans.
What did the research involve?
The researchers were interested in developing a drug that could block the action of a transcription factor called NOTCH1. Mutations can cause this transcription factor to be active when it shouldn’t be, which can lead to a form of leukaemia called T-cell acute lymphoblastic leukaemia (T-ALL).
Inside the cell, a protein called MAML1 binds to a complex of proteins that contains the NOTCH1 transcription factor. Laboratory tests have shown that a fragment of the MAML1 protein (called dnMAML1) can block the action of NOTCH1 in T-ALL leukaemia cells, stopping them from dividing.
However, protein fragments (peptides) may not be structurally robust, and may be susceptible to changing shape or being broken down. Research has suggested that peptides can last longer in the body and bind to other proteins more effectively if they are bonded to a chemically altered amino acid (the building blocks of proteins). This technique is called hydrocarbon stapling.
The researchers investigated whether a hydrocarbon-stapled form of dnMAML1 would still be able to block the action of NOTCH1. They designed six shorter hydrocarbon-stapled pieces of protein similar to dnMAML1, referred to as SAHM1, SAHM2 etc.
They examined how long these SAHMs took to get into the cell and selected those that looked most promising for further testing. They observed how well SAHMs bound to the complex of proteins that contained NOTCH1. They also looked at the effect of SAHMs on genes that are normally switched on by NOTCH1, and their effects on T-ALL cells in the laboratory. Finally, they looked at what effect the most promising SAHM had on a genetically engineered mouse model of T-ALL.
What were the basic results?
Laboratory tests on cells
The researchers found that some of the SAHMs, including SAHM1, were able to enter cells. SAHM1 could bind to the complex of proteins containing NOTCH1. SAHM1 also reduced the activity of genes in T-ALL leukaemia cells that would normally be switched on by NOTCH1. Treating T-ALL cells in the laboratory with SAHM1 stopped the cells from dividing as often as they normally would.
The researchers found that mice with progressive T-ALL that were given twice-daily SAHM1 injections experienced a reduction in the number of cancerous cells. Once-daily SAHM1 injections had a lesser effect, and T-ALL leukaemia progressed in untreated mice.
How did the researchers interpret the results?
The researchers concluded that the hydrocarbon-stapled peptide SAHM1 caused “potent, NOTCH-specific anti-proliferative effects” in both cells grown in the lab and the mouse model of T-ALL leukaemia. They say that their SAHM1 molecule should be useful in working out the role of NOTCH1 in normal and diseased tissues. It also provides a starting point for developing targeted drugs to treat NOTCH-related cancers and other conditions.
This study has developed a new method for targeting the NOTCH1 transcription factor. The technique may eventually lead to the development of new drugs for T-ALL and other Notch-related conditions. However, this will be a long-term goal as much more animal and human research will be needed to determine the effectiveness and safety of this new approach.