Why Anti-Angiogenesis Treatment Fails
An Exciting Cancer Treatment Hasn’t Fully Lived Up to its Promise -- University of Toronto Researchers Offer A New Explanation
A new study led by University of Toronto researchers has provided the first evidence that tumours can thwart a type of drug called angiogenesis inhibitors by stealing blood vessels from neighbouring healthy tissues.
The findings, published April 8 in the Journal of the National Cancer Institute, could explain why some tumours stop responding to treatment.
“In order for a cancer to grow beyond the size of a pinhead, it needs to keep making more blood vessels,” says senior author Robert Kerbel, a professor in the Faculty of Medicine’s Department of Medical Biophysics.
Blood vessels supply oxygen and nutrients to tumours. By preventing new blood vessels from forming (a process known as angiogenesis), drug treatments can prevent the cancer from growing and spreading to other parts of the body. But tumours almost always develop resistance to the treatments.
To understand why, Kerbel and his graduate student, Elizabeth Kuczynski, focused on hepatocellular carcinoma (HCC), a type of liver cancer for which there is only one approved therapy: the antiangiogenic drug sorafenib. While 35 to 43 per cent of HCC tumours initially can be controlled by the drug, they inevitably develop treatment resistance. “Sorafenib is a very toxic drug. When tumours respond patients get a benefit, but there are side effects and they always stop responding,” says Kerbel, who is also a senior scientist at the Sunnybrook Research Institute.
Working with researchers in Toronto and the U.K, Kerbel showed that the sorafenib-resistant HCC tumours relied on existing blood vessels in the neighbouring healthy liver tissue instead of forming new blood vessels to sustain its growth.
“These tumour cells are really clever,” says Kerbel. “They’re usurping the normal blood vessel network that is present in these organs.” In contrast, HCC tumours that were held in check by sorafenib relied solely on new blood vessels generated through angiogenesis.
By stealing existing blood vessels, a process known as vessel co-option, tumours don’t need to develop their own, rendering antiangiogenic therapies ineffective.
The researchers also found the sorafenib-resistant HCC tumours underwent a genetic switch that enabled the tumour cells to become more mobile and infiltrate adjacent tissues. Their findings provide important insight into how tumours become resistant to treatments and identify two new potential drug targets—the switch from angiogenesis to vessel co-option and the co-opted blood vessels themselves.
“Maybe you could do something that will delay that switch, so that instead of happening after three months it happens after three years,” says Kerbel. “That would have an effect on prolonging patient survival.”
