An international team of researchers at VIB-KU Leuven, Belgium, the UK Dementia Institute and Children’s Cancer Institute, Australia, have identified a novel therapy for T-cell acute lymphoblastic leukaemia (T-ALL). This therapy, which targets the gene most frequently mutated in T-ALL, markedly slows the progression of this type of leukaemia, with minimal toxicity to normal tissues.
The research article, which was published this week in the journal Science Translational Medicine,was co-authored by Dr Roger Habets at Leuven Institute for Neuroscience and Disease and Dr Charles de Bock of Children’s Cancer Institute.
Two diseases, one target
The new therapy targets a gene called NOTCH. This is the most frequently mutated gene in the T-ALL sub-type of leukaemia, with NOTCH mutations found in around 60% of patients.
NOTCH sends growth signals to leukaemia cells, causing them to multiply uncontrollably. However, to do this, the NOTCH protein must first be cut in half. The cutting is done by an enzyme ‘scissor’ called gamma-secretase. This makes gamma-secretase an attractive drug target. If it can be inhibited, NOTCH can be rendered inactive.
Coincidentally, the gamma-secretase enzyme also plays an important role in Alzheimer’s Disease. Knowing this, scientists developed drugs that targeted gamma-secretase, as a potential treatment for Alzheimer’s. Unfortunately, when these drugs were tested in clinical trials, they caused severe side effects, particularly in the gut. Clinical trials ceased.
The problem is that gamma-secretase exists in four different forms, some of which are essential for normal cell functioning. Previous drugs targeting gamma-secretase inhibited all four complexes, thus producing side effects in normal cells.
Selectivity is the solution
The research team wanted to see if they could find a solution to that problem in the context of T-ALL. First, they investigated whether there were any differences in the relative amounts of the four gamma-secretase complexes in these leukaemia cells, compared to normal cells.
They discovered that T-ALL cells only have two of the four enzyme complexes. These are the ones containing a component called PSEN1 – the pink building block in the image above.
Next, they treated T-ALL with a new, more selective drug against gamma-secretase, called MRK-560. MRK-560 only inhibits the two complexes containing PSEN-1, leaving the other two complexes to function as usual.
They found that MRK-560 markedly reduced the induction and progression of T-ALL in their mouse models of leukaemia, without affecting normal T-cell development. Just as importantly, it didn’t produce the usual gut toxicity associated with previous non-selective gamma-secretase inhibitors.
This study thus provides evidence that targeting the PSEN1 subset of gamma-secretases could be an effective and safe therapeutic option for patients with T-ALL.
Towards a new therapy for T-ALL
Dr de Bock, who recently moved from Belgium to head his own Team at Children’s Cancer Institute, is optimistic that this class of drugs can be rapidly moved into the clinic:
“Historically, these types of drugs have had very limited success, since patients did not tolerate the toxicity in normal tissues,” Dr de Bock said.
“We provide the first proof of concept that selective targeting of a specific version of the gamma-secretase complex is effective and safe, suggesting this strategy’s potential for translation.”
Read the research article.
Top image: the four different gamma-secretase complexes (Image credit: Luk and Idoya,Somersault1824 https://www.somersault1824.com/about/)