Mechanistic studies of NOTCH signalling and the development of novel targeted NOTCH inhibitors

Abstract

Our bodies are made up of billions of cells that must constantly communicate for tissues to function properly. One key communication system is the NOTCH signalling pathway. When this pathway malfunctions, it can contribute to diseases such as cancer and rare hereditary disorders. In my research, I studied three examples of this.

First, I investigated how NOTCH controls the growth of new blood vessels. I discovered how two proteins, JAG1 and DLL4, interact, and developed a mathematical model that predicts how cells decide their roles in this process. This model provides us a new tool to test targeted predictions.

Next, I focused on T-cell leukaemia, which driven by an overactive NOTCH1 receptor. I found that the NOTCH1 receptor must pair with itself to become active, and I designed peptides to block this pairing. In cells from leukaemia patients and in zebrafish embryos, these peptides suppressed the growth and spread of cancer cells.

Finally, I studied CADASIL, a hereditary brain disease caused by mutations in NOTCH3, for which no treatment currently exists. I showed that mutant NOTCH3 proteins clump together only when produced alongside normal proteins, and used a similar approach to develop inhibitors that block this clumping.