Therapeutic potential of Notch inhibition in T-cell acute lymphoblastic leukemia: rationale, caveats and promises

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy that presents with poor prognosis. Treatment relies on the application of aggressive therapies that produce deleterious side-effects, justifying the quest for novel, more efficient and selective molecular targeting agents. Mutations leading to abnormal Notch-1 activity are present in more than half of the T-ALL patients, underscoring the potential therapeutic relevance of targeting Notch-1 inhibition and further reinforcing the need to better comprehend the mechanisms by which Notch-1 drives T cell leukemogenesis. Clinical application of γ-secretase inhibitors to block Notch signaling in T-ALL revealed new challenges that involve improvement of the therapeutic benefit and reduction of intestinal toxicity. Here, we review the latest advances in the development and use of Notch antagonists and summarize the current knowledge on Notch function in T-ALL to understand how it may translate into novel therapeutic strategies that increment the efficiency of Notch inhibition.

Keywords::

• γ-secretase inhibitors
• Notch
• NRR-directed Notch-1 antibodies
• SAHM1
• T-ALL

Acknowledgement

The authors thank Daniel Ribeiro for kindly preparing the figures.

Financial & competing interests disclosure

Leonor M Sarmento is a recipient of a fellowship (BPD/41244/2007) from Fundação para a Ciência e a Tecnologia (FCT), Portugal. The work in the laboratory of João T Barata that relates to this review was supported by the grants PTDC/SAU-OBD/69974 and PTDC/SAU-OBD/104816 from FCT. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.