Surgery News - March 2008 - (Page 17) MARCH 2008 • SURGERY NEWS PRACTICE TRENDS Judah Folkman: Visionary Extraordinaire His theory on tumor growth was ridiculed, but he persevered until research proved its truth and value. B Y M I C H E L E G. S U L L I VA N Else vier Global Medical Ne ws r. Judah Folkman, the man who changed medicine’s fundamental understanding of tumor growth, has left a legacy reaching well beyond his early research on colorectal cancer, to cardiovascular disease, ophthalmology, dermatology, and even obstetrics. While initially disregarded and even ridiculed, his hypothesis that tumors recruit their own vascular network has generated a vast field of research that his colleagues say is only beginning to bear fruit. A host of antiangiogenic cancer drugs has been approved in the last 4 years and more are sure to follow, along with potential treatments in many other areas of medicine. “I think many of us looked on him as a kind of Moses, leading our field into our promised land,” said Dr. Herbert Hurwitz, lead investigator of the clinical trial that silenced Dr. Folkman’s critics by showing that inhibition of angiogenesis could improve survival in patients with metastatic colon cancer. “We can see that land now, and I am very happy that Dr. Folkman got to enter into it—at least a little bit.” Dr. Folkman, 74, died Jan. 14 at the Denver International Airport while on his way to a scientific conference in Vancouver, B.C. He was the director of the vascular biology program, Andrus Professor of Pediatric Surgery, professor of cell biology at Children’s Hospital Boston, and the 2006 recipient of the Jacobson Innovation Award of the American College of Surgeons. News reports quoted the family as saying he had suffered an apparent heart attack. Few clinical observations have affected so many areas of medicine as did the one Dr. Folkman made 40 years ago, while he was looking at rabbit thyroids in glass containers. He wasn’t studying cancer, eye disease, or any of the other areas that benefitted from that eureka moment long ago. Dr. Folkman, who was working at the Naval Medical Research Institute, was just trying to keep the rabbit organs going with an investigational acellular blood substitute. He observed that the tumor cells implanted in the thyroids all stopped growing at the same tiny size, but these same cells caused cancer when they were delivered to a live mouse. An unknown factor that was driving the tumor’s growth in the animal was clearly absent in the artificial environment. Dr. William Li, a former student of Dr. Folkman and the founder of the Angiogenesis Foundation in Cambridge, Mass., recounted the story: “His hypothesis was that perhaps a tumor’s growth depended on recruiting its own blood supply, and that if this was true, then there might be a brand-new way to stop that growth by cutting off the formation of these new vessels and starving the tumor.” Dr. Folkman unleashed this radical idea at Harvard Medical School and chief of ophthalmology at Massachusetts Eye and Ear Infirmary, both in Boston. “He started this work because of his in10 years later in a seminal paper (N. Engl. terest in cancer, but it wasn’t long before J. Med. 1971;285:1182-6). He showed that he realized it had much broader implicatumors grown in the anterior chamber of tions,” she said. In the early 1990s, Dr. Miller and Dr. Ana rabbit’s eye, beyond the reach of any blood vessels, stayed tiny, whereas those thony Adamis, who was then also in the implanted in the vascularized iris grew department of ophthalmology at Harvard Medical School, collaborated with Dr. rapidly. Some molecular signal was driving that Folkman on a series of experiments with growth, Dr. Folkman postulated, and stop- the newly discovered vascular endothelial growth factor (VEGF). This work identiping it might stop tumors as well. fied VEGF as the Professional cenagent responsible for sure was swift and ocular neovasculartotal, his colleagues ization after ischemic have recalled in inor other insults in terviews. “The idea proliferative diabetic of angiogenesis was retinopathy and agemet with ridicule related macular deand derision because generation. it challenged orthoBut the team met doxy,” Dr. Li said. with skepticism. “We According to preactually had trouble vailing wisdom, the getting our first panest of blood vessels per published besurrounding aggrescause people just sive tumors wasn’t didn’t believe VEGF anything special. Bycould be that imporproducts of tumor tant,” Dr. Miller said. cell die-off were “At our first big eye thought to dilate exresearch meeting, we isting host vessels, were the last presenand no one believed tation of the last afthat attacking the DR. FOLKMAN ternoon. I think vasculature would there were about eight people there, and have any therapeutic benefit. But all the negative comments did not six of them were friends.” But 2 years later at that same meeting, shake Dr. Folkman’s belief or his commitment to proving it. Over the years, his a packed ballroom listened to work that generated ranibizumab (Lucentis), a tenacity became legendary. “His perseverance was remarkable,” VEGF inhibitor that can preserve sight said Dr. Larry Norton, deputy physician- and even improve vision in a third of pain-chief for breast cancer programs at tients with age-related macular degenerMemorial Sloan-Kettering Cancer Center, ation, which is the leading cause of blindNew York. “He experienced not just a few ness in elderly Americans. “This is the first time that real vision months or a few years, but years and years during which no one at all accept- improvement has ever been shown in a substantial percentage of patients with ed this idea.” “Yet he continued to pursue it in the lab this blinding disease,” commented Dr. and speak about it, even when he received Miller. While angiogenic and angiostatic comno positive feedback from the medical community. He never changed his ideas to pounds were being tested for their thergain social acceptance or funding. It was apeutic potential in a variety of diseases, vision that drove him, and it was some- cancer remained the Holy Grail. In the mid-1990s, Dr. Folkman’s lab rething beautiful.” The methods used by Dr. Folkman were ported that endostatin blocked angioalso impressive. There were no tools to genesis and regressed primary tumors in study blood vessel growth at the time, Dr. mice to microscopic dormant lesions Li said, so Dr. Folkman had to invent what without any toxic side effects (Cell 1997; 88:277-85). he needed. Endostatin and angiostatin entered clin“He made these remarkable accomplishments with rudimentary technolo- ical trials in the late 1990s, and by 1998, a gy,” said Dr. Hurwitz, cochair of gas- wave of antiangiogenic drugs was being trointestinal oncology at Duke University studied, according to Dr. Li: 46 for cancer, Medical Center, Durham, N.C. “The more 5 for macular degeneration, 1 for diabetrudimentary your technology, the more ic retinopathy, and 4 for psoriasis. The insight you need to design the ‘killer ex- next year was just as exciting, with 5 new periment,’ because technology won’t solve antiangiogenics entering trials for coronary artery disease, 5 for peripheral vasthe problem for you.” By the mid-1980s, Dr. Folkman and cular disease, 1 for stroke, and 10 for others were discovering angiogenic and wound healing. Other laboratories were unable to repliantiangiogenic compounds. Already it was clear to him that the new class of cate Dr. Folkman’s findings, however, and drugs could have an enormous impact in early trials were negative. He continued many areas, recalled another colleague, his quest, undaunted for the most part by Dr. Joan Miller, chair of ophthalmology these failures, said Dr. Otis Brawley, chief medical officer of the American Cancer Society. “The only time I ever saw him down was after he got word of a large budget cut that really hurt his grant. But for the most part, his attitude was, ‘Let’s do what we have to do to move this forward.’ He was always enthusiastic about what was coming next.” Not until Dr. Hurwitz’s landmark presentation at the 2003 meeting of the American Society of Clinical Oncology did opinion turn in favor of angiostatic drugs. The phase III trial added bevacizumab (Avastin) to a standard therapy for metastatic colon cancer. It was the first to show that an antiangiogenic agent could significantly prolong survival, adding months of life at the median. A year later, bevacizumab won Food and Drug Administration approval for advanced colorectal cancer. Last year was a stellar one for antiangiogenic cancer drugs, said Dr. Brawley: “In 2007, we had four new cancer drugs approved by the FDA, and three of them were antiangiogenics.” The oncology drugs mostly have benefited patients who failed first-line treatment. New research will soon describe their place in early cancers, said Dr. Nancy Davidson, president of the American Society of Clinical Oncology. “They have largely been used in advanced cancers in partnership with other therapies, and we have seen improved outcomes—sometimes improved survival and sometimes a prolonged period of progression-free survival,” she said. “Where they would have more impact is if they could be applied strategically in early cancers with the hope of reducing recurrence. I think this will be the research focus over the short to moderate term,” Dr. Davidson said. In 1998, the New York Times quoted Nobel laureate Dr. James Watson hailing Dr. Folkman as the man who would cure cancer. Although Dr. Folkman never asserted that, and tried to downplay the prediction, drugs that combat angiogenesis are making a difference in the lives of cancer patients. “They have improved how long patients live with their cancer and how well they live with their cancer. That is a clear and major deliverable from the angiogenesis hypotheses,” Dr. Hurwitz said. “The issue of whether patients are cured is less clear. But more effective treatments employing antiangiog
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