Signs and signals:
Notch it up or down?
By Brona McVittie
Maria Dominguez works on a related signaling pathway called Notch. “Notch is very important in development as well as in adult tissue,” she says. “This pathway plays a role in the growth of solid tumours in the breast, prostate and pancreas, but also in leukemia.” Cancer of the blood involves overcrowding of bone marrow with abnormal cells that can spill over into the bloodstream and spread throughout the body.
As with other pathways, Notch involves detection of signals by a protein receptor on the cell surface. This receptor internalises the signal and feeds it through to the cell nucleus, where it activates genes controlling self-renewal, proliferation and programmed cell death. Mutations in Notch components can lead to overactive signaling and subsequently cancer.
Learning about Notch has prompted a series of clinical trials with drugs that quash the pathway. Gamma-secretase inhibitors (GSIs) have been used to this end with varying success, “But the enzyme they inhibit plays a role in more than just the Notch signaling pathway,“ explains Maria, whose team of researchers and collaborators at the University of Columbia recently confirmed that quashing Notch with GSIs is not a foolproof therapeutic strategy for leukemia.
“Notch is not only important in cancer. It plays a role in cardiovascular and neurodegenerative disease. Notch tends to be overactive in cancers, but reduced in degenerative diseases. GSIs were originally developed to treat Alzheimer’s,” says Maria. They inhibit the build up of amyloid plaques in the brain by hampering the role of a different enzyme, but they affect Notch signaling too.
So what new cancer therapies can we expect in the next decade? “What has become easier in the last year is more precise diagnostics”, reassures Michael Boutros. “With reference to signaling pathways there are many ways to cause cancer in a cell. That’s a lead for the future and therapy will become much more individualized applying drugs to damaged signaling components on a case-by case basis.”