New Ideas About Anti-Angiogenesis
The traditional goal of anti-angiogenic therapy has been to kill all of a tumor’s blood vessels and choke the tumor to death. The problem, however, is that the drug doses needed to completely starve a tumor in patients can be harmful to some normal tissues, like our cardiovascular system. Even the FDA-approved drug Avastin given in low doses has been shown to lead to cardiac problems in some patients. To choke a tumor to death, the dose of Avastin would have to be so high that it might not be safe. That's one reason why Avastin is combined currently with chemotherapy to kill as many cancer cells as possible.
I proposed in 2001 that if we use the optimal dose and schedule of anti-angiogenic drugs, we can destroy some blood vessels and make the remaining vessels closer to normal—I named them “normalized blood vessels.” My thinking was that Avastin would work better if given with chemotherapy because we could get the chemotherapy through the normalized vessels to more regions of the tumor.
But there’s one more important reason why Avastin works better in patients when combined with chemotherapy. When a tumor’s blood vessels are abnormal and the flow shuts down in a region of the tumor, the oxygen levels in that region fall below the normal levels. Now, you might think in your mind, “Well, lowering oxygen levels is good news. If cancer cells are in a hypoxic [low-oxygen] environment, how can these cells grow? They need oxygen.” Except, unfortunately, because of genetic mutations, some cancer cells thrive in this environment. What is worse is that the more hypoxia there is, the more malignant cancer cells become. They become more aggressive and more metastatic.
So our thinking was that if we could make tumor blood vessels more normal, or organized, the oxygen levels would go up toward normal levels, and the pressure on the cancer cells to become more malignant would be reduced.
A major obstacle to effective radiation therapy is hypoxia. So I also believed that this increase in oxygen levels would make radiation therapy more effective. This was in 2001. As soon as I proposed this idea, I encountered tremendous resistance from the scientists and physicians working on cancer biology and treatment.
The usual response was, “Look, we’ve been told for 30 years that if we gave anti-angiogenic therapy, we would starve the tumor to death. Now you're telling us you are going to make the blood vessels function better?”
To prove this theory, I did two things: My colleagues and I conducted preclinical studies in mice. In the back of my mind, I thought that even if we obtained supportive evidence in mice, the skeptics still wouldn’t believe me. They’d say, “Well, this is in mice. You can always cure cancer in mice. We've known that for some time. What about in patients?” So my colleagues and I initiated clinical trials in parallel with the preclinical studies.