Title:Gamma Secretase Inhibitor: Therapeutic Target via NOTCH Signaling in T Cell Acute Lymphoblastic Leukemia
Volume: 22
Issue: 15
Author(s): Bhupendra Kaushik, Dilipkumar Pal*Supriyo Saha
Affiliation:
- Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, C.G., 495009,India
Keywords:
γ-secretase inhibitor, T-ALL, NOTCH1, mutation, cancer, targeted therapy.
Abstract:
Background: T-cell acute lymphoblastic leukemia (T-ALL) is a diseased condition of
bone marrow and lymphoblast, mainly expressed on T-cell immune phenotype. Diagnosis of TALL
patients shows the burden of a large tumour and leukemia cells in the peripheral blood vessel
which often infiltrates into the central nervous system.
Objective: Chemotherapy is considered the primary mode of treatment for this disease, but recent
advancements in the molecular understanding of the disease, including NOTCH1 signaling, could
offer some alternatives. NOTCH signaling undergoes a non-regulated mutation at NOTCH1 in
most T-ALL. Gamma-secretase (GS) plays a key role in blocking of proteolytic activation of
NOTCH receptors, which could potentially be a new targeted therapy for this type of leukaemia.
This study mainly aims to outline the role of γ-secretase inhibitors via NOTCH signaling in TALL.
Results: The role of GSI (γ-secretase inhibitor) in most T-ALL cell lines has been linked to the targeting
pathway of NOTCH signaling. Mutation at NOTCH1 has however not served as a predictor
of γ-secretase inhibitor sensitivity because of several factors, including gene expression of NOTCH
pathway activity. Therefore, despite the promising outcome of this approach in NOTCH-1 activated
T-ALL, not all patients with this condition are expected to respond.
Conclusion: Long-term therapeutic success against cancerous cells is rarely achieved with
monotherapy, and even targeting investigational pathways such as NOTCH may require a combination
regimen. Ultimately, the optimised use of these new therapeutic agents may become the next
tool in our search for an effective ‘individualized medicine’.
