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.
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