Blood vessel growth (green) in a mouse cornea can increase when the Notch switch is dysfunctional. Decoy drugs target these switches to slow angiogenesis during cancer progression. (Credit: Laboratory of Jan Kitajewski, Columbia University Medical Center)
Cancer cells are shifty characters. They use a number of dirty tricks to survive and infiltrate the body. Now Columbia University Medical Center (CUMC) scientists are fighting back with some sneaky strategies of their own. A study published in Cancer Discovery describes how Jan Kitajewski, PhD, and colleagues have created new decoy drugs that can intercept the deceptive growth signals that cancer cells send out.
As tumors grow, they consume increasing amounts of oxygen and nutrients. Eventually cancer cells need their own blood supply, and release signals that interact with the lining of existing blood vessels, in effect putting out a call for new vessel growth. This process, called angiogenesis, involves switches that direct how and where the vessels are formed. To prevent cancers from co-opting the blood supply, scientists have created drugs that block some of these switches, including an important one called Notch. Notch plays a key role in angiogenesis and contributes to the progression of many different types of cancers.
There’s a significant problem with Notch-targeted drugs, however: like many chemotherapy treatments, they are blunt weapons. Turning off Notch may slow cancer growth at one site, but can cause problems for many other kinds of cells that rely on Notch to control normal processes. As a result, current Notch-targeted drugs provoke a range of significant side effects including intestinal and liver toxicity. To mitigate these problems, doctors have to give patients complex drug cocktails.
Dr. Kitajewski’s team at CUMC may have devised a more effective strategy. Instead of trying to block Notch outright, the lab has engineered molecules that mimic part of the switch, preventing certain types of signals from activating it. These molecules act as decoys, jamming signals at the surface of blood vessel cells, and interfere with tumor angiogenesis.
In tests on mice with different types of cancer, these decoy drugs caused only moderate toxicity compared with Notch-blocking treatments. Why the improvement? The decoys interfere with the signals that are more prevalent in tumors, but they don’t block the entire switch. As a result, Notch can continue to communicate in normal tissues as needed.
“Scientists can now design drugs more strategically because we are learning so much about the complex molecular details behind a cancer’s growth,” said Dr. Kitajewski, who is a professor of Obstetrics & Gynecology at CUMC. “As a result, future drugs will be able to target cancer sites with greater precision and with fewer side effects.” His lab will continue to improve the design of the decoy drugs before it moves on to testing them in clinical trials.