Modulation of Oncogenic NOTCH Signaling in Highly Aggressive Malignancies by Targeting the γ-Secretase Complex: A Systematic Review - PubMed
6 hours ago
- #cancer therapy
- #NOTCH signaling
- #γ-secretase inhibitors
- NOTCH receptors play a crucial role in carcinogenesis by regulating gene expression through the release of the NOTCH intracellular domain (NICD).
- γ-secretase inhibitors (GSIs) are evaluated for their anticancer potential, focusing on blocking tumor progression, targeting cancer stem cells, and overcoming therapy resistance.
- A systematic review of 69 articles (60 preclinical, 9 clinical) highlights GSIs' synergy with chemotherapy and radiotherapy, especially in NSCLC, melanoma, and TNBC.
- Common GSIs like DAPT and RO4929097 enhance efficacy of drugs such as gemcitabine, paclitaxel, and 5-FU in various cancers.
- Clinical trials with GSIs, particularly RO4929097, show limited efficacy due to tumor heterogeneity, dosing issues, and non-selective inhibition.
- Future strategies include receptor-specific NOTCH inhibitors, patient stratification, and combination with immunotherapy, CRISPR, CAR-T cells, and targeted delivery systems.
- Emerging research focuses on the tumor microenvironment, immune evasion mechanisms, and AI-driven personalized medicine to improve outcomes.