Unraveling disparate roles of Notch-1 and Notch-2 signaling in bladder cancer

Bladder cancer is the fifth most common cancer, yet it remains understudied and we are only now making strides in understanding it’s molecular make-up. Recently we and others have discovered that loss of the cell surface receptor Notch-1 drives growth of some bladder cancers, while increased Notch-2 activity drives growth of other bladder cancers. Here we aim to determine how Notch-1 and Notch-2 can lead to such differing effects on cancer growth even though they share many features. From this we aim to design a new drug to inhibit Notch-2.

We will:

• Create a mouse model that over-expresses Notch-2 in the bladder. We expect this will cause bladder tumours to form.
• Use advanced techniques to study the differences between Notch-1 and Notch- 2 signaling that make them have such different effects. We will especially investigate how each Notch protein controls the reading of genes in the cell nucleus.
• Develop a new a new drug to inhibit Notch-2 using computer-aided drug design.

End of Award Update – April 2024

Results

We have identified a candidate Notch-2 inhibitor that requires further testing in pre-clinical models before potential testing in patients with bladder cancer.

Impacts

Our work has explained an important pathway that drives growth and progression of bladder cancer in some patients.

Potential Influence

This new inhibitor could represent a novel way to treat bladder cancer.

Next Steps

We will publish the results on Notch when completed.