Therapeutic Targeting of Notch Signaling: From Cancer to Inflammatory Disorders

Abstract

Over the past two decades, the Notch signaling pathway has been investigated as a therapeutic target for the treatment of cancers, and more recently in the context of immune and inflammatory disorders. Notch is an evolutionary conserved pathway found in all metazoans that is critical for proper embryonic development and for the postnatal maintenance of selected tissues. Through cell-to-cell contacts, Notch orchestrates cell fate decisions and differentiation in non-hematopoietic and hematopoietic cell types, regulates immune cell development, and is integral to shaping the amplitude as well as the quality of different types of immune responses. Depriving some cancer types of Notch signals has been shown in preclinical studies to stunt tumor growth, consistent with an oncogenic function of Notch signaling. In addition, therapeutically antagonizing Notch signals showed preclinical potential to prevent or reverse inflammatory disorders, including autoimmune diseases, allergic inflammation and immune complications of life-saving procedures such allogeneic bone marrow and solid organ transplantation (graft-versus-host disease and graft rejection). In this review, we discuss some of these unique approaches, along with the successes and challenges encountered so far to target Notch signaling in preclinical and early clinical studies. Our goal is to emphasize lessons learned to provide guidance about emerging strategies of Notch-based therapeutics that could be deployed safely and efficiently in patients with immune and inflammatory disorders.

Comprehensive Integrated Single-Cell Whole Transcriptome Analysis Revealed the p-EMT Tumor Cells—CAFs Communication in Oral Squamous Cell Carcinoma

“…As a result, medicines that block or promote NOTCH signaling may be particularly useful depending on the situation. For example, NOTCH inhibitors such GSI (Gamma-Secretase Inhibitor) and MK-0752 for solid tumors have been tested in Phase I clinical trials, resulting in stable disease [ 42 , 43 ]. EMT and tumor cells’ invasiveness in various malignancies were also enhanced by collagen-rich CAFs.…”

S-Adenosylmethionine Inhibits Colorectal Cancer Cell Migration through Mirna-Mediated Targeting of Notch Signaling Pathway

“…In addition, the overexpression of Notch signaling has been found to be associated with poor prognosis or poor response to treatment of some solid tumors [ 5 , 7 ]. Therefore, therapeutic strategies have first been developed in the preclinical phase and in early-phase clinical trials to target oncogenic functions of Notch in tumor cells [ 8 ]. Recent findings highlighted a central role for abnormal Notch in CRC and indicated a correlation between the overexpression of Notch signaling components and CRC progression and metastasis [ 9 ].…”

Semaphorin 6D as an independent predictor for better prognosis in clear cell renal cell carcinoma

“…4 E). The Notch signaling pathway is involved in various inflammatory diseases and cancers [ 16 , 17 ]. The KEGG pathway enrichment analysis showed that it was one of the most altered pathways.…”