Tumors can’t grow any larger than the size of a pinhead unless the body generates a network of new blood vessels to nourish them – a process known as angiogenesis. So using drugs called angiogenesis inhibitors to block this process is an ingenious strategy with many potential advantages over standard chemotherapy.
Indeed, when the first such drugs entered testing in the late 1990s, there was great hope –and much hype.
Angiogenesis inhibitors are unlike most cancer therapies in that they don’t directly attack cancer cells in hope of killing them. Instead, they attack tumors’ blood supply with the aim of choking off their nourishment. As tumors grow, they exhaust their oxygen supply and send out signals to nearby blood vessels begging them to sprout new, small vessels to feed the cancer. Angiogenesis inhibitors block those signals in an attempt to starve the tumor.
Because their attack is focused on tumors’ blood supply, angiogenesis inhibitors generally don’t harm normal cells. As a result, their side effects are generally milder than those associated with chemotherapy. And because they don’t attempt to directly kill tumor cells, they are less likely to cause drug resistance, as is common with many cancer treatments.
The first angiogenesis inhibitor drug approved for cancer treatment was Avastin (bevacizumab), in 2004. A monoclonal antibody, Avastin binds to an angiogenesis signaling protein called VEGF (vascular endothelial growth factor) and prevents it from stimulating angiogenesis in nearby blood vessels. It has been approved to be used alone in glioblastoma brain tumors, and in combination with other drugs to treat metastatic colorectal cancer, some non-small cell lung cancers, and metastatic kidney cancer.
Other approved drugs with antiangiogenic effects include Nexavar (sorafenib), Sutent (sunitinib), Votrient (pazopanib), and Afinitor (everolimus). Dana-Farber’s Early Drug Development Center (EDDC) initiated testing for many of these drugs, which were subsequently tested in the Kidney Cancer program, where their activity has led to FDA approval. Several new agents continue to be tested in early phase clinical trials, notes Geoffrey Shapiro, MD, PhD, director of the EDDC.
While they have proved a valuable addition to the anti-cancer armory, and have been shown to extend lives in some cases, angiogenesis inhibitors haven’t been the “silver bullet” they once were predicted to be. For one thing, they are useful only in cancers that form solid tumors – not blood cancers like leukemia. An unanswered question is how they should be used in the long term. In some cases, the drugs shrink tumors, but in others they merely halt further growth. This may mean that angiogenesis inhibitors will need to be taken long-term, or even for life.
Experience has shown they can have serious side effects. Among them: a risk of internal bleeding; holes in the digestive tract; increased blood pressure, interference with normal wound healing, and the risk to a developing fetus if used to treat a pregnant woman. Nonetheless, these side effects are manageable.
Additionally, these agents may be particularly useful in combination with other therapies. For example, Shapiro says, anti-angiogenesis agents may augment the effects of chemotherapy in lung and colon cancers. Recently, in a Dana-Farber-led study, the combination of an anti-angiogenesis agent with a PARP inhibitor strikingly improved the clinical outcome of patients with ovarian cancer compared to a PARP inhibitor alone. Finally, anti-angiogenesis agents may also improve the efficacy of drugs designed to activate the immune system to fight cancer. Such combinations are actively being tested in Dana-Farber’s Center for Immuno-Oncology.
These are still early days and as researchers learn more, and develop new angiogenesis inhibitors, they will define how large a role this strategy can have in treating cancer.