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.

Keywords: Notch; Notch ligands; cancer; immune system; inflammation.

FIGURE 1

Overview of the Notch signaling pathway. The Notch signaling pathway operates between four cell surface Notch receptors (Notch1-4) and four agonistic Notch ligands from the Jagged (Jag1, Jag2) and Delta-like families (Dll1, Dll4). Mechanisms of Notch activation and canonical signaling are depicted along the following steps: (1) A furin-like protease cleaves the Notch receptor into a transmembrane heterodimer during its transit to cell surface through the Golgi complex (S1 site); (2) Ligand-receptor binding generates a physical force onto the extracellular domain of the Notch receptor, allowing ADAM10-mediated proteolysis at the S2 site which is normally hidden within a “negative regulatory region” of the receptor; (3) ADAM10 generates a membrane-bound intermediate that becomes rapidly sensitive to intramembrane proteolysis by the γ-secretase complex (S3 site). As a result, intracellular Notch (ICN) is released into the cytoplasm and translocates into the nucleus. (4) ICN binds with the DNA-binding protein RBP-Jκ (also known as CSL); (5) ICN and RBP-Jκ recruit a member of the Mastermind-like (MAML) family of transcriptional coactivators via the N-terminal MAML alpha-helical domain; (6) In turn, MAML proteins recruit other transcriptional co-activators (CoA) and p300, respectively, to enhance transcription of Notch target genes.

FIGURE 2

Genetic and pharmacological approaches to Notch inhibition. (A) Genetic inactivation strategies leading to inhibition of the Notch signaling pathway are represented by red “X” with the exception of dnMAML, where the red “X” depicts the disruption of the Notch transcription activation complex due to expression of a truncated, dominant negative (dn) form of MAML1. In addition to conditional expression of dnMAML, commonly used approaches include conditional inactivation of Notch ligand genes, Notch receptor genes, Adam10, genes encoding components of the γ-secretase complex or Rbpj; (B) Strategies of pharmacological inhibition of Notch signaling either though the administration monoclonal antibodies targeting the Notch ligands or receptors, or small molecule inhibitors. γ-secretase inhibitors target components of the γ-secretase complex. CB-103 inhibits the Notch transcription complex.