Notch Self-Renewal Inhibitors

The Notch pathway is highly conserved and involved in both cell proliferation and apoptosis. There are five ligands involved: Delta-like ligand 1 (DLL1), DLL2, DLL4, Jagged 1 (JAG1), and JAG2. When the ligands bind to the Notch receptor, the intracellular domain (NICD) is cleaved by ADAM, a disintegrin and metalloproteinase as well as γ-secretase (Wong et al. 2019). After NICD is released, it is able to bind to a translational complex and initiate transcription of proteins that either influence proliferation or apoptosis. Vascular endothelial growth factor (VEGF) signaling also contributes to tumor angiogenesis and works in collaboration with Notch ligand DLL4 to further the cancerous phenotype. More specifically, overexpression of ligands DLL4 and JAG2 have been found in pancreatic adenocarcinoma (Gao et al. 2017). Targeting of both these ligands, as well as VEGF, is therefore crucial in halting self-renewal of PaCSCs. It has been shown that elevated expression of DLL4 leads to therapeutic resistance against VEGF receptors, making a synergistic approach to targeting these two more appealing (Takebe et al. 2015). The bispecific antibody targeting DLL4 and VEGF receptors, Navicixizumab, is currently under clinical trial for colorectal and ovarian cancer, and the PancreAss Kickers plan to incorporate it into their treatment as well (OncoMed Pharmaceuticals 2018). A similar bispecific antibody to target overexpressed JAG2 and VEGF receptors can also be developed and incorporated into the treatment to stop the self-renewal PaCSC process.