Belgian researchers have successfully developed an approach to selectively target Notch signalling in T-cell acute lymphoblastic leukaemia (T-ALL), to reduce the toxicity previously associated with this strategy.
Notch signalling is frequently implicated in T-ALL, and researchers have previously attempted to block gamma-secretase, an enzyme which activates Notch. However, current inhibitors of this enzyme caused severe gastrointestinal side effects.
The gamma-secretase complex consists of four protein subunits, two of which exists in different versions. Existing gamma-secretase inhibitors (GSIs) targeted all versions of the complex equally, which could be the cause of the toxicity. So a research team, led by Jan Cools and Bart de Strooper, explored whether inhibition of specific versions could reduce side effects.
The team from VIB-KU Leuven in Belgium, UK Dementia Institute, and Children’s Cancer Institute in Australia, showed that their targeted approach was effective and safe in mice and human cancer cells.
An inhibitor which selectively targeted the PSEN1 subunit of gamma-secretase was found to significantly reduced the leukaemia burden in mice carrying patient-derived T-ALL cells. Crucially, this inhibitor did not appear to cause the same gastrointestinal toxicity associated with broad spectrum GSIs.
The findings are published in the journal Science Translational Medicine.
Dr Charles de Bock, co-first author of the study with Dr Roger Habets, says: “Historically, these types of drugs have had very limited success, since patients did not tolerate the side effects in normal tissues. 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.
“If this approach would indeed work for patients with T-cell acute lymphoblastic leukaemia, this could open up the door for other types of cancer as well. Safe, selective gamma-secretase inhibition might even be useful as an additional therapy in a variety of other disorders in which Notch signalling is deregulated.”
Source: Habets, R.A., de Bock, C.E., Serneels, L., Lodewijckx, I., Verbeke, D., Nittner, D., Narlawar, R., Demeyer, S., Dooley, J., Liston, A., Taghon, T., Cools, J., de Strooper, B. (2019) “Safe targeting of T-cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition”, Science Translational Medicine, available from doi: 10.1126/scitranslmed.aau6246
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