More Insights on the Use of γ‐Secretase Inhibitors in Cancer Treatment

Autor: Javier Santos, Laura González-Sánchez, Pilar López-Nieva, María Ángeles Cobos-Fernández, Raúl Córdoba, José Fernández-Piqueras
Přispěvatelé: UAM. Departamento de Biología, Genética Susceptibilidad en Cáncer y en Enfermedades Psiquiátricas, Ministerio de Ciencia, Innovación y Universidades (España), Fundación Ramón Areces, Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Banco Santander
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Cancer Research
Broad-Spectrum Γ-Secretase Inhibitors
Hematologic Malignancies
Resistance
Apoptosis
MYC
medicine.disease_cause
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Secretase Inhibitors
0302 clinical medicine
Challenges
Receptor
Notch1
Receptor
Broad-Spectrum ?-Secretase Inhibitors
biology
Receptors
Notch
PF‐03084014 treatment
Targeted Therapy
New Resistance Factor
Biología y Biomedicina / Biología
T-Cell Lymphoblastic Cell Lines
Oncology
030220 oncology & carcinogenesis
Contributes
Broad-Spectrum
PF-03084014 treatment
Notch Pathways
Signal Transduction
Programmed cell death
Broad‐spectrum γ‐secretase inhibitors
medicine.drug_class
Cells
Down-Regulation
Monoclonal antibody
T‐cell lymphoblastic cell lines
PF-03084014
Selective ?-Secretase Inhibitors
03 medical and health sciences
Cell Line
Tumor
medicine
PTEN
Humans
Myc Gene Dosage
Cell Lymphoblastic Cell Lines
business.industry
Mechanism (biology)
Rational design
Cancer
medicine.disease
Selective γ‐secretase inhibitors
New resistance factor
030104 developmental biology
Selective Γ-Secretase Inhibitors
MYC gene dosage
Mutation
biology.protein
Cancer research
Amyloid Precursor Protein Secretases
business
Carcinogenesis
Zdroj: The Oncologist
Biblos-e Archivo. Repositorio Institucional de la UAM
instname
Digital.CSIC. Repositorio Institucional del CSIC
ISSN: 1549-490X
1083-7159
Popis: The NOTCH1 gene encodes a transmembrane receptor protein with activating mutations observed in many T‐cell acute lymphoblastic leukemias (T‐ALLs) and lymphomas, as well as in other tumor types, which has led to interest in inhibiting NOTCH1 signaling as a therapeutic target in cancer. Several classes of Notch inhibitors have been developed, including monoclonal antibodies against NOTCH receptors or ligands, decoys, blocking peptides, and γ‐secretase inhibitors (GSIs). GSIs block a critical proteolytic step in NOTCH activation and are the most widely studied. Current treatments with GSIs have not successfully passed clinical trials because of side effects that limit the maximum tolerable dose. Multiple γ‐secretase–cleavage substrates may be involved in carcinogenesis, indicating that there may be other targets for GSIs. Resistance mechanisms may include PTEN inactivation, mutations involving FBXW7, or constitutive MYC expression conferring independence from NOTCH1 inactivation. Recent studies have suggested that selective targeting γ‐secretase may offer an improved efficacy and toxicity profile over the effects caused by broad‐spectrum GSIs. Understanding the mechanism of GSI‐induced cell death and the ability to accurately identify patients based on the activity of the pathway will improve the response to GSI and support further investigation of such compounds for the rational design of anti‐NOTCH1 therapies for the treatment of T‐ALL. Implications for Practice γ‐secretase has been proposed as a therapeutic target in numerous human conditions, including cancer. A better understanding of the structure and function of the γ‐secretase inhibitor (GSI) would help to develop safe and effective γ‐secretase–based therapies. The ability to accurately identify patients based on the activity of the pathway could improve the response to GSI therapy for the treatment of cancer. Toward these ends, this study focused on γ‐secretase inhibitors as a potential therapeutic target for the design of anti‐NOTCH1 therapies for the treatment of T‐cell acute lymphoblastic leukemias and lymphomas.
Understanding the mechanism of γ‐secretase inhibitor (GSI)–induced cell death and the ability to accurately identify patients based on the activity of the pathway could improve the response to GSI therapy for the treatment of cancer. This article focuses on γ‐secretase inhibitors as a potential therapeutic target to treat T‐cell acute lymphoblastic leukemias and lymphomas.
Databáze: OpenAIRE
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