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ABSTRACT
Introduction: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the therapy of ALL has significantly improved, the heterogeneous genetic landscape of the disease often causes relapse, which is difficult to treat. Achieving a positive outcome for patients with relapsed or refractory ALL remains a challenging issue. The high prevalence of NOTCH-activating mutations in T-cell acute lymphoblastic leukemia (T-ALL) and the central role of NOTCH signaling in regulating cell survival and growth of ALL provide a rationale for the development of Notch signaling-targeted strategies in this disease. Therapeutic alternatives with effective anti-leukemic potential and low toxicity are needed.
Areas covered: This review provides an overview of the currently available drugs directly or indirectly targeting Notch signaling in ALL. Besides considering the known Notch targeting approaches, such as γ-secretase inhibitors (GSIs) and Notch inhibiting antibodies (mAbs), currently in clinical trials, we focus on the recent insights into the molecular mechanisms underlying the Notch signaling regulation in ALL.
Expert opinion: Novel drugs targeting specific steps of Notch signaling or intersecting pathways could improve the efficiency of the conventional hematological cancers therapies. Further studies are required to translate the new findings into future clinical applications.
Article highlights
Notch signaling activation sustains T-ALL leukemogenesis, whereas its role is controversial in B-cell malignancies.
A number of approaches to inhibit different steps of Notch signaling activation are in preclinical development, aimed to enhance the positive outcome of conventional T-ALL treatments.
Impairment of post-translational processes regulating Notch signaling could be a potential therapeutic strategy for the treatment of T-ALL.
Targeting the epigenetic machinery regulating Notch signaling activity would need to be investigated as an alternative approach to impair Notch-driven oncogenic program in T-ALL.
Some natural compounds have been shown to act as Notch inhibitors and to display anti-proliferative activity in cancer cells, thus representing putative novel therapeutic agents.
Several reports highlight the efficacy of combinatorial Notch-targeted therapies in hematological cancers.
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Declaration of interest
The author have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.