All cancer drugs share a problem: They penetrate just a few cells into the tumor. Now a team of biologists has identified a molecule that helps cancer treatments dive deep into tumors, at least in mice. The approach still needs to be tested in people, but if it pans out, it will circumvent one of the biggest challenges in the field. “This has huge implications for cancer therapy,” says David Cheresh, a tumor and vascular biologist at the University of California (UC), San Diego, who was not involved in the work.
Tumors keep drugs at bay in two ways. First, their vessels are not leaky enough to allow drugs inside. And second, they have high hydrostatic pressure. This means that fluid tends to flow away from tumors, not toward them, and that “any drug has to swim upstream, if you will,” says Erkki Ruoslahti, a cell and tumor biologist at the Sanford-Burnham Medical Research Institute in Santa Barbara, California. Last year, Ruoslahti and two scientists in his lab, Kazuki Sugahara and Tambet Teesalu, reported on a new peptide, a small molecule called iRGD, that seemed to do a good job of getting inside tumors when it was anchored to a cancer drug.
Now the three, along with several colleagues, have tested iRGD with a variety of cancer therapies in mice. The researchers found that administering iRGD along with several common cancer drugs significantly increased how much each drug entered a tumor, between seven and 40 times as without the peptide. It also helped reduce the drug dose: about one-third as much drug needed to be given to be effective. That’s important because toxicity often makes it tough to administer high doses of chemotherapy that might help. The group focused especially on human breast, pancreatic, and prostate tumors grafted into mice.
Ruoslahti thinks that iRGD can tackle both the tight blood vessels and the high fluid pressure. The peptide apparently manages this by first hooking up to receptors on a tumor's blood vessels, then it binds to another receptor on tumor cells that regulates permeability of their vascular system. In work published last year, researchers demonstrated that iRGD needed to be chemically connected to any given cancer therapy—making it much more difficult to develop it as a drug. In the new work, published online today in Science Express, the researchers report that the peptide can be given simply at the same time as the drug.
Drugs failing to get into tumors “is a huge problem for cancer in general,” especially when disease appears in the brain, which is even less accessible, says Zena Werb, a cell biologist at UC San Francisco. Werb cautions, however, that “it’s rather early” to tell how promising iRGD is. Cheresh points out that one risk is that the peptide could spawn new metastases by opening up tumor blood vessels and helping cancer cells to slip out. Still, they agree that if iRGD’s safety and effectiveness pan out, it could revolutionize cancer treatment for patients with all sorts of tumors. Ruoslahti is pushing it forward; he and his colleagues have filed patent applications on the peptide and are now in discussions with drug companies about testing it in humans.