300 Longwood Avenue Boston, MA 02115 (617) 355-6000 Research: Judah Folkman on angiogenesis Dr. Judah Folkman, director of the Program in Vascular Biology at Children's Hospital Boston, and professor of Pediatric Surgery and Cell Biology at Harvard Medical School, originated the groundbreaking idea that angiogenesis is also central to the development and growth of tumors. When this idea first came to light 45 years ago, there was no conceptual framework for understanding it, and few people were actively studying blood vessel formation. Today, after a long trip made in small increments, it is widely accepted that a tumor cannot grow beyond a certain size without recruiting new blood vessels to feed it without angiogenesis. In these interviews, conducted between the fall of 2005 and the fall of 2007, Dr. Folkman discusses the history of angiogenesis in cancer research, where the research is headed, and he recounts a couple of personal anecdotes. QuickTime (version 7 or higher) required to view clips. [Get QuickTime] Fall 2007 Angiogenesis update Dr. Folkman gives an update of advances in the field of angiogenesis over the last five years. [03:22 -- 4.8 Mb]     View the clip...   What's to come In this clip, Dr. Folkman tells where he thinks the field of angiogenesis is going in the years to come. [02:14 -- 3.2 Mb]     View the clip...     Working at a children's hospital Working with neurosurgeons in developing a treatment for hydrocephalus is one example of the benefits of working at a children's hospital. [02:45 -- 3/9 Mb]     View the clip...   Fall 2006 Angiogenesis overview Dr. Folkman provides a brief overview of the field, discussing its origins, recent developments and what we can expect in the years to come. [00:45 -- 1.2 Mb]     View the clip... Fall 2005 Angiogenesis and cancer Dr. Folkman talks about angiogenesis, treating cancer with angiogenic inhibitors, and recent improvements in anti-cancer drugs. [04:21 -- 12.7 Mb]     View the clip...   1972 -- First milestone: Growing endothelial cells Until this time, growing the cells outside the body was assumed not possible. [01:02 -- 3 Mb]     View the clip...     1975 -- Next big step: Isolating angiogenic factors With the help of a chemical engineer from MIT, Dr. Folkman and colleagues were able to find the first protein that caused blood vessels to grow. [01:28 -- 4.2 Mb]     View the clip...     1980 -- First identification of an angiogenesis inhibitor Dr. Folkman and colleagues find that the protein interferon alpha prevents blood vessels from growing. [00:56 -- 2.7 Mb]     View the clip...     Reversing blindness Angiogenesis research has lead to a cure for macular degeneration. [01:03 -- 3 Mb]     View the clip...     "Professor-genesis" Children's Hospital Boston has a reputation for cultivating many professors. Here's how this has come about. [01:41 -- 4.8 Mb]     View the clip...     "Rabbi-like doctor" Dr. Folkman tells the story of how he decided to become a doctor, and his father's reaction to the news. [02:07 -- 6.2 Mb]     View the clip...     House calls with Dr. Koop An apprenticeship with C. Everett Koop results in long-distance house calls. [01:20 -- 3.9 Mb]     View the clip...   Transcript (Fall 2005 interview) Angiogenesis and cancer We in the medical profession are absolutely tied to knowing the name of a tumor and its position -- its anatomical position -- before we can treat it. But we no longer do that with Lipitor where we treat or prevent heart attacks and we really don't have to know the anatomical position of the plaques. But we did; not now. And we are no longer tied to knowing the position or the type of infection; we often just treat the white blood count and so forth. So the question is, can you treat cancer like that? And the answer is not clear, but we think there is a way to do that. Title: In order to nourish themselves, cancerous tumors create their own blood supply, a process called angiogenesis When tumors switch on angiogenesis -- that idea came in the 90s -- when they switched on angiogenesis from having been non-angiogenic for years, everyone's assumed that that's permanent. And now we've found that about five percent can switch it off and go backwards, and they're doing it all the time, but you can't tell because most of the tumor cells are angiogenic, so the tumor goes on. Growing 60, 70, 80 percent of its cells are angiogenic but the small group is switching backward -- going to non-angiogenic. So that's a very important reversal of angiogenesis. So nature can do it -- we would just like to increase the percentage. Title: Treating cancer with angiogenesis inhibitors Well I think they'll be used, first of all, more and more widely in combination. Right now, of course, they have to be tested alone, with chemotherapy and without it, and gradually they're being combined, because the inhibitors we have are tremendous breakthroughs, but they are generally very narrow. So they'll treat, for example, VEGF or one angiogenic factor. But tumors keep adding things -- they keep using different angiogenic factors, proteins -- and it will be useful to combine these. And after the profession learns that experience -- in the 40s they used penicillin by itself, and you wouldn't do that today -- you'd use penicillin plus something else, or even three drugs. Then the next step will be to move over to the very broad angiogenesis inhibitors. None of them are in the clinic yet, but they've been discovered, and caplostatin is one and endostatin is another. And there are 26 others in the body. Title: Improvements in anti-cancer drugs The angiogenesis inhibitors are approved in 28 countries now, besides the U.S. We're learning that there are very few side effects, so the patients are finding it very comfortable to be treated for cancer. That's the first huge change -- and they do not want to go back to any other treatments. So we have patients who play golf, get their strength back enough to go back to work, and yet are being treated everyday with an angiogenesis inhibitor. The second thing we've found is that there's less drug resistance than with standard chemotherapy. So they can keep taking these drugs. Patients have been on thalidomide for five years for multiple myeloma, on Endostatin for three and a half years for other tumors, so that's very exciting to the oncologist. And the third thing is that, when you have treatment that's relatively non-toxic, so that you can give it for long periods of time -- like tomoxin. It raises the question of whether, if you could diagnose the tumor really early -- by a blood test, looking for a biomarker, or in a urine test, looking for a biomarker -- that maybe you could treat the blood test, even though you never saw the tumor. This is all in the future, but you have to imagine what it might be and see if you can get there. First milestone: Growing endothelial cells The first big milestone was in '72, when we first were able to grow endothelial cells that lie in the blood vessels. They had never been alive outside the body -- no one could get them to grow. It was assumed it was not possible. It was assumed by everyone in the field that they had to live in blood, and therefore, if you put them in a dish and added blood, how could you see them? That was a big problem. And so Michael Gimbrone, when he was a medical student working in the lab -- he's now a professor at the Brigham -- succeeded in getting them to grow, that was very exciting. And then after that, people began to use those to begin to study what controls the growth of these cells. The next big step: Isolating angiogenic factors They didn't believe there were any angiogenic proteins or any angiogenic inhibitors, that you couldn't find an inhibitor unless you had a simulator, and it seemed a lot, in 1975, the field was ending. And Bob Langer came and was a brand new chemical engineer graduate from MIT, top of his class, and I showed him the problem and he thought for a few minutes and he said, "I can solve that." And he solved it by inventing or creating a small polymer material that would slowly release the protein when implanted into the cornea, like a microdot, and it was not irritating to the cornea, and sure enough, blood vessels grew right to it. Wherever we moved it the blood vessels would find it, if the protein was the correct one, and that led to the eventual purification of the first angiogenic protein, which is basic FGF. So that moment in '75 that we could do that, and the protein later, those were two highlights. So then people began to believe that there might be angiogenic proteins from tumors, and the next problem was how could you turn these off, and so we began the search for angiogenic inhibitors. First angiogenesis inhibitor identified: Interferon alpha We began the search for angiogenesis inhibitors, and the very first one was in 1980, and it's an old protein -- it's interferon alpha. It circulates in all of us at very low levels. We found with Bruce Zetter -- he was a post-doctoral fellow at the time -- found that interferon alpha could inhibit endothelial cells from moving. And that led to discoveries later that interferon was anti-angiogenic. So from 1980 to now -- that's 25 years -- eleven were discovered, and many of those are in clinical trials. Reversing blindness In macular degeneration, where blood vessels grow in the back of the eye, a disease that affects 12 million Americans which has never been successfully treated before, and you go blind first in one eye and two years later in the other eye, because of bleeding of these vessels, now angiogenesis inhibitors are being used. One's approved already, and a second one is about to be approved -- and it is the second one that is related to Avastin -- they're actually getting sight to come back. And in fact, this is going so fast -- because they can see the result right away -- within a month the patients can get their sight back, that you don't have to wait for a tumor to regress over a couple of months, or for metastasis to regress, and the patients aren't sick, so the eye studies are showing us in a telescopic way -- very fast -- what's going to happen in the future of cancer. "Professor-genesis" Different labs are run differently, and sometimes the tradition is that you have post docs come for two years, and they leave and you don't promote anyone from within. So you just keep bringing people in and sending them off. We do both, but we've spend a lot of time mentoring the young people to: 1) instill scientific self confidence, so that they can be on their own sooner rather than later, and also trying to urge them to really think about very fundamental problems and not stay on problems that are too trivial. And also we give them maximum amount of credit, every single time. I take my name off papers very early in their career, usually after the second or third paper. And always talk about them, show their pictures, give the credit, so that they can do the same for their own students. And many, many of them now are professors of whom we are very proud, around the world. One of the students wrote to me one time that, your lab does angiogenesis and "professor-genesis," because we're really always trying to see how far our students can go in their careers. And it's been very exciting to watch. "Rabbi-like doctor" Starting very early, my father -- who was a rabbi -- had a very large congregation, and there were three of us -- my brother, sister, and I -- and when we reached the age of six or seven, if we were well behaved during the previous week, the family rule was that we were awarded by being invited to accompany him on his hospital rounds to see the sick members of the congregation, which was Saturday and Sunday, when he would go around. And they were all in oxygen tents because they had had heart attacks. And so he would pray by the oxygen tents, and also talk with them, and we would sit very quietly. So when I was seven I asked him, "Why doesn't a patient mind that you're bringing your children?" He said, "It's very therapeutic, because they said if they were really dying, he wouldn't bring around the kids." So then I also noticed that, after a couple of years doing this, that the doctors could come in and open the tents, but dad couldn't do that. And they could do things -- adjust the tubes. So one day when I was seven or eight, I told -- I'm the oldest in the family, so I was expected to be a rabbi, it was just assumed -- I told dad with great trepidation that I think I'm not going to be a rabbi, I am going to be a doctor. And he said, without even blinking, he said, "So you can be a rabbi-like doctor." I thought this was very astute because it meant that he was backing it and not opposing it. And then all the rest of my medical career -- when I was in medical school, also in the hospital -- so I could call him when, like a patient with Down syndrome baby would ask "Why would god do this to me?" And so I would call dad, and he would have these phenomenal and helpful pieces of advice. House calls with Dr. Koop When I had been elected to come to Children's, I had had a lot of pediatric surgical training from Doctor Hendren, who was at the Mass General. But Koop called -- he was the surgeon and chief of Philadelphia Children's, and he said that he would offer another half year of training that would be very intensive training -- that it will be an apprenticeship and we won't tell anyone that you're a professor. We'll just say you're a resident. And that's what we did. And he was tremendous because he would come in and operate with me day and night, and taught all of his skills, and he also made house calls -- Thursday nights he made house calls. So he would call up at six o'clock and say to get someone to cover for you. And he would call up two patients -- some were in Pennsylvania, not too far, but he could get back to Philadelphia, but they were way out in Lancaster -- who had children who had bad cancer. And he would make a house call. And that way he could talk to the whole family. And he could teach more than just the surgery. So you rode out with him and rode back with him, and I was back by midnight. Every Thursday. Amazing. Support Dr. Folkman's research To learn how you can support Dr. Folkman's research, please contact Joan Romanition, Director of Development, Folkman Angiogenesis Research Institute: (617) 355-2429. The information on this website should not be taken as medical advice, which can only be given to you by your personal health care professional. Copyright © Children's Hospital Boston. All rights reserved.