Researchers at the Washington University School of Medicine have found limitations to an experimental cancer treatment.

These findings are critical within the medical community because they offer doctors new insight into choosing cancer treatment methods.

David Piwnica-Worms and Raphael Kopan, professors of developmental biology at the medical school, co-authored a study investigating the safety of anti-Notch therapy. They concluded that the therapy could have potentially fatal side effects.

Anti-Notch therapy is used to treat some forms of cancer. It targets the Notch pathway, which is composed of a gene and gene product whose proteins produce receptors that are expressed on the surface of cells.

While expression of Notch1, a key protein in the pathway, is essential for the normal development of many cellular types, Notch1 also has cancer and anti-cancer properties.

Depending on the cell type, Notch1 can either enhance or inhibit tumor growth. When its tumor-suppressant effects are destroyed, there can be medical implications for cancer patients.

Piwnica-Worms and Kopan sought to understand the biology of the Notch1 receptor using a mouse model.

In human patients with two copies of the Notch1 gene, both copies, in most cases, must be knocked out, or destroyed, to allow cancer cells to grow. This is known in the medical field as the two-hit hypothesis. Following this principle, Piwnica-Worms and Kopan introduced a mutation that affected both Notch1 genes in mice.

One of these genes—the null—was intentionally knocked out. The researchers monitored the mice over time to determine what would happen when the second gene was eventually inhibited.

“We had an unbiased genetic approach to look at a loss of heterozygosity, meaning the loss of that one gene—a second hit,” said Piwnica-Worms. “And in an unbiased way, we could survey the animals over their lifetime to find out what was going to happen, and it ended up that these vascular tumors formed.”

In mice, the dominant effect of the second hit was in blood vessels in the liver. Tumor growth was not suppressed, which instigated the proliferation of vascular-based tumors.

“Even though it could’ve happened anywhere, the most common place for that second gene to be knocked out was in the vascular cells,” added Piwnica-Worms. “Which given the role that Notch has in the growth of blood vessels maybe wasn’t a surprise.”

Although some of these tumors were benign, mice bled to death when tumors popped.

The outcome of this study raises issues with the long-term use of anti-Notch therapy. Doctors use drugs to inhibit the function of these genes in humans. If patients have chronic exposure to these Notch inhibitors, the study predicts that they will develop vascular problems and other potentially serious side effects. In grave cases, tumors can form, rupture and cause patients to suffer internal hemorrhage.

“There might be measured short-term use that might be able to avoid those side effects,” Piwnica-Worms said, “but it certainly raises a flag of caution for chronic use of Notch inhibitors.”