An international team of researchers at VIB-KU Leuven, Belgium, the UK Dementia Institute and the Children’s Cancer Institute, Australia, have found a safer treatment for a specific type of leukaemia, thanks to lessons learned from research into Alzheimer’s disease.
By refining a therapeutic avenue that was previously abandoned because of its severe side effects, the team – including UK DRI Director Bart De Strooper – came up with a targeted approach that was both effective and safe in mice and in human cancer cells. The findings revive hope for translation to leukaemia patients and have been published on 29 May in Science Translational Medicine.
T-ALL—short for T-cell acute lymphoblastic leukaemia—is a form of cancer characterised by the presence of too many immature white blood cells. “T-ALL mainly affects children and is rapidly fatal if left untreated. Current chemotherapy is very effective but causes long-term side effects, so there is an urgent need for less toxic targeted therapies for these young patients,” says leukaemia expert Prof Jan Cools (VIB-KU Leuven).
One of the biological pathways frequently involved in T-ALL is Notch signalling. Earlier research efforts were geared towards blocking the enzyme gamma-secretase, which cleaves and activates Notch. Unfortunately, these gamma-secretase inhibitors proved to be too toxic for clinical use because of side effects in a variety of healthy tissues.
Lessons from Alzheimer’s disease research
Researchers and clinicians investigating treatments for Alzheimer’s disease have been very interested in blocking gamma-secretase as well, because it is also involved in the processing of amyloid-beta, which is linked to neurodegeneration. Alzheimer specialist Prof Bart De Strooper (VIB-KU Leuven, UK DRI) who co-lead the current study with Jan Cools has had a long interest in the activity of gamma-secretase.
“It is important to realise that gamma-secretase is actually a complex consisting of four protein subunits, two of which exists in very different versions,” says Bart De Strooper. “Clinical trials have been performed with broad-spectrum, non-selective inhibitors that target all different versions of the complex equally.”