Folkman's reputation in the medical world was well established long before he hit the headlines. The son of a rabbi, he was a student when he developed the first implantable atrio-ventricular pacemaker in the 1950s. Later, he pioneered the first implantable polymers to obtain slow drug releasing. At the age of 34, when he became the youngest professor of surgery to be hired at the Harvard Medical School, he was already studying ways to block the formation of new blood vessels--a process called angiogenesis--to stop tumor growth. His ideas, initially met with skepticism by oncologists, are today the basis for an area of research that is attracting enormous interest. At least 20 compounds with an effect on angiogenesis are now being tested in humans for a range of pathologies that include cancer, heart disease and vision loss [see "Keep Both Eyes on the Blockers"]. But the premature hype continues to generate disproportioned hopes among the press, the public and the stock market. Recently, we met Folkman in his laboratory at the Childrens Hospital in Boston to ask about his work and the progress of clinical trials on endostatin and angiostatin.--Sergio Pistoi and Chiara Palmerini
What makes anti-angiogenesis drugs a promising strategy in cancer therapies?
Many experiments showed that tumor growth and metastasis are angiogenesis-dependent. Tumors cannot grow unless they recruit their own private blood supply. That is why microvascular endothelial cells [the cells lining capillaries], which are essential for new blood vessel growth, have become an important target in cancer therapy. Antiangiogenic compounds do not attack the tumor cells directly, as chemotherapies do. Instead they turn endothelial cells off, so they wont make new blood vessels, and the tumor will eventually stop growing. The effect of angiostatin and endostatin is tumor-specific. So you have very few, if any, adverse effects on the organism. Targeting endothelial cells has some advantages: these cells are genetically stable, meaning that they do not mutate. In contrast, tumor cells tend to mutate and in this way they often become drug-resistant. Therefore, development of acquired drug resistance, which is common with chemotherapy, is less likely with angiogenesis inhibitors. Moreover, each endothelial cell can support up to 100 tumor cells; that means that by knocking out just few endothelial cells you have an effect on hundreds of tumor cells.
What impact did the sudden celebrity have on your daily work?
At the beginning I felt an enormous pressure. Patients were calling at all times and many flew to Boston. We hired three people just to answer the patients' and media's queries around the clock. [The news] raised expectations and demand for angiogenesis inhibitors before these drugs had completed testing in clinical trials. On the other hand, there are many patients alive today because they were treated with antiangiogenic drugs: thalidomide for multiple myeloma or low-dose interferon alpha for giant cell bone tumors or for angioblastomas. For any new type of therapy, there is always a dilemma about when to inform the public. If its too early, then physicians are besieged by calls from patients for drugs that cannot be obtained. If too late, then critics say that hope was destroyed for patients with advanced disease. Our own research work was temporarily impacted because of many phone calls, but in the long run the effect was minimal.
The first tests in humans with endostatin began two years ago. What are the results so far?
The rules of clinical trials for endostatin are the same that the FDA sets for any other cancer drug. In the phase one of the trial you are only allowed to start with very few patients, for which any other option has failed, slowly increasing the dose in order to test the drugs safety. All phase I studied have shown that both endostatin and angiostatin are very well tolerated and have virtually no side effects. This is the most exciting thing about these drugs. On average a patient cannot stay on chemotherapy for more than six weeks, because either there are too many side effects or the tumor escapes [becomes resistant to the treatment]. So far, no patient has been reported to [have to] stop endostatin because of adverse reactions. Furthermore, there were some patients whose disease became stable, and they regained their energy and weight. In few patients, there was also a slow tumor regression. [Results were reported in May at the meeting of American Society of Clinical Oncology and in the Journal of Clinical Oncology, September 2002 ]. Last spring endostatin moved to phase II to test its efficacy in rare neuro-endocrine tumors of the pancreas. [Other phase II trials started in May (endostatin for metastatic melanoma) and July (angiostatin and chemotherapy for non-small cell lung cancer).]
Still, these results are very far from the dramatic improvements that you observed in mice. Why is it so difficult to replicate the experiments in humans?
Well, first of all these [Phase I] experiments are primarily designed to test a drugs safety, not its efficacy. Then, when you experiment with mice you can increase the dose, give different drugs in combination, and choose on which tumors and at what stage you want to try them. With humans, of course, the rules are strict: you can only give a single drug to patients with very advanced tumors, starting at very low doses. For example, we found the most dramatic effects in mice when endostatin and angiostatin were used in combination, but the FDA will not allow to use both drugs together before the end of phase II, maybe early phase III [large-scale, with many human patients] of the trials. Moreover, we have evidence that the drugs would work better if given at an early stage of the tumor. Another complication is that each tumor puts out different amounts of angiogenic stimulators. Some breast cancers, for instance, make only one angiogenic factor while others make six. That means that you have to balance the dose against a specific tumor, as much as you would adjust the dose of insulin according to your blood sugar levels for diabetes. But this is not the way you do clinical trials. You cant start with the dose you think is effective for each patient: everyone has to stay on a fixed schedule. But we are beginning to learn that when the drugs are approved--I dont know how many years that will be--a physician wont just stay on the same dose no more than you do with penicillin.
After endostatin and angiostatin were first hailed as the miracle cure, now many say that they are not meeting the expectations. How do you feel about all the ups and downs of your work in the press?
I feel that these drugs are not much different than any drugs going through clinical trials. Expectations are not the same for everyone. For example, researchers may have different expectation than the public or the press. Suppose that you read the abstract of phase I endostatin trial saying that the drug has shown "linear pharmacokinetics." It is a very good finding for an early trial, because it means that blood levels of the drug directly correlated with increasing doses, as predicted. But the same report can be deceiving for the public. Its very hard for reporters to explain the many hurdles of clinical testing of any new drug and its hard for the public to understand that, on average, most drugs take seven to 10 years to be approved. Expectations are also biased by decades of experience with classic chemotherapy. With chemotherapy you expect to see a fast tumor regression, because the drugs directly kill the cancer cells; but it doesnt work this way for angiogenesis inhibitors, which are designed to turn off the blood supply, so that the tumor gradually slows down and, eventually, stops growing.
Do you think that clinical trials for antiangiogenic drugs should follow different rules?
No. The current guidelines for clinical trials are based on determining safety and efficacy and are working well. However, we must not forget the differences between anti-angiogenic therapy and conventional chemotherapy. Some definitions, for example, do not have the same value. One example is the term "stable disease." For conventional chemotherapy it usually means "failure," because it may not last long and may be accompanied by many side effects and a poor quality of life. In contrast, for anti-angiogenic therapy, patients with stable disease have virtually no symptoms and there is less of a risk of drug resistance if they are treated for a long time. Some patients refer to this situation as "having cancer without disease." In this case, the term "stable disease" has a completely different meaning.
Are you involved in the clinical trials of endostatin and angiostatin?
Trials are being carried on at centers in Boston; Houston, Tex.; Madison, Wis.; and Amsterdam and Utrecht in the Netherlands under the supervision of experienced oncologists. I have not participated directly. However, our laboratory has helped to develop some of the blood tests that are being evaluated in these trials and I help oncologists to design the trials.
What are your expectations for the future of these drugs?
My vision is that without any major side effect or resistance these drugs could be used in combination with other drugs or radiation therapy virtually lifelong. For the long term, over the next five to 10 years, we can ask whether the risk of drug resistance and the harsh side effects of treating cancer can be reduced, and whether cancer can ever be converted to a chronic manageable disease like diabetes or heart disease.
Sergio Pistoi is a freelance science reporter based in Arezzo, Italy. He can be found at www.greedybrain.com
Chiara Palmerini is a staff science writer for the Italian weekly magazine Panorama.
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