NOVA Online | Cancer Warrior | Dr. Folkman Speaks

Dr. Folkman Speaks
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NOVA: It took just as long to find angiogenesis inhibitors, those that inhibit blood-vessel growth, right?

Dr. Folkman: Yes. In 1980 came interferon, in 1981 or 1982 came platelet factor 4. These were the first two. By then we said there are angiogenesis inhibitors.

NOVA: And a member of your team found the third one by accident?

Don Ingber had the presence of mind to study a curious contaminant rather than simply dispose of it.

Dr. Folkman: Yes. Don Ingber was an M.D., Ph.D. who had come up from Yale and was studying endothelial cells. Every time a new building was being built outside Children's Hospital, funguses would come into the windows, and you'd get contamination of these in the cell cultures. When you got a fungus growing in there, it would turn turbid, and the little dish of cells would all die and float.

So Don had a set of endothelial cells, and there was a fungus contaminant at one end of the dish. He called me and said you have to come in and see this, because there's something different. The cells were not dying, they were just backing away. He said there's something diffusing, something coming from the fungus that is stopping the endothelial cells.

Now, what's important is that anyone else in the lab would have thrown that out. There were signs all over the lab that said if your cell culture becomes contaminated with a fungus, you must throw it out, because if you try to keep it and treat it, it will infect the whole lab. I used to get upset with people who didn't, so Ingber called and said I would like permission to keep this culture.

A fungus that contaminated Ingber's cultures lead to the angiogenesis inhibitor known as TNP470.

That led to the isolation of a compound that is today in clinical trial. The whole purification was done by Takeda Chemical Industries, because they are very good at growing funguses. They made the chemical which is today called TNP-470, Takeda neoplastic product #470. It's in clinical trial, and in animal tumors it has a very broad spectrum antitumor effect. It was a little stronger than platelet factor 4 and much stronger than interferon. So that was a purely serendipitous discovery. [For other unplanned-for finds in medicine, see Accidental Discoveries.]

NOVA: Two angiogensis inhibitors your team discovered—endostatin and angiostatin—are now in clinical trials [see Designing Clinical Trials]. How do you feel about the patients who are trying your new therapy?

Dr. Folkman: Patients going through these trials are in a desperate situation. Nothing else has worked, there's little time left—and they have a fast clock running. We all have a clock but theirs is very fast. And so they're very scared. Therefore, from a physician's point of view, you have to go out of your way to make sure that not only they understand but that you don't destroy their hope.

NOVA: A friend of mine keeps asking me, since these people in clinical trials are terminally ill, why don't you give them a lot of, say, endostatin?

Dr. Folkman: What if a lot turns out to be dangerous? Then you've made their life worse than it was. The ethic is "above all do no harm." To build on that rule, an old rule in medicine, the Food and Drug Administration through federal laws have said when you start a new drug, you must start much lower than you expect it to be effective. That is the safe thing to do. But it creates an ethical problem that that might be an ineffective dose.

NOVA: And even with larger doses, you don't want to raise anyone's hopes too high.

Watch clip of Judah Folkman on "raising expectations."
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Dr. Folkman: Yes. Many times when you see the very first experiments in mice and then you try it in people, there's always a great deal of hope among patients and physicians that it will be an improvement. It's the same problem we have with endostatin and angiostatin. But there's also a high risk of let-downs or raising expectations too high. Because when you go from the laboratory to people, there's a high failure rate. All mice are identical twins; all people are not.

Our view is that in time angiogenesis inhibitors will be added to chemotherapy, added to radiotherapy, added to immunotherapy, added to gene therapy, and added to one another. And eventually, one by one, doctors will have a whole arsenal of these, and that may improve things. We hope. But the excitement of the discovery of them comes across sometimes too much when you're trying to explain it.

Among Dr. Folkman's hopes for anti-angiogenesis drugs: There will eventually be many varieties of them, and they will help usher in an era of decreased toxicity and drug resistance.

NOVA: What are your biggest hopes?

Dr. Folkman: The best hopes for the field or these drugs is they're going to be many. If endostatin or angiostatin should fail, the principles are solid, they've been established over 30 years. They've been replicated over 30 years by laboratories around the world, and other laboratories are making more and more discoveries based on the principles. Demonstrating proof of principle in the clinic that you can control tumors or slow them down or regress them by anti-angiogenic therapy is the hope—that's what we're working on. Eventually we hope that that will come, even if it means that you have to give two angiogenesis inhibitors together, because that's what we have to do in mice to get a really good tumor eradication. So physicians in the next decade may have an arsenal of angiogenesis inhibitors, possibly 10 or 20, and they can combine them and choose among them and add them to other therapies to increase the power of the control that doctors have over cancer.

The other hope is that the toxicity will come down, that there will be less and less over the years of the punishing toxicity that patients have to put up with now. (That happened in infection. In the 1930s we had arsenic, which is really toxic. Then we had sulfur in the late `30s—less toxicity. Then we had penicillin in the `40s, really low toxicity.) A third hope is that drug resistance will gradually disappear, because now that's the biggest problem in cancer therapy.

Dr. Folkman Speaks | Cancer Caught on Video
Designing Clinical Trials | Accidental Discoveries | How Cancer Grows
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