细胞急性淋巴细胞白血病中通过 NOTCH 信号传导的治疗靶点

Title:Gamma Secretase Inhibitor: Therapeutic Target via NOTCH Signaling in T Cell Acute Lymphoblastic Leukemia

Volume: 22 Issue: 15

关键词: γ-分泌酶抑制剂、T-ALL、NOTCH1、突变、癌症、靶向治疗。

摘要:

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’.

Cite this article as:

Gamma Secretase Inhibitor: Therapeutic Target via NOTCH Signaling in T Cell Acute Lymphoblastic Leukemia, Current Drug Targets 2021; 22 (15) . https://dx.doi.org/10.2174/1389450122666210203192752