THE FLAP OVER ANGIOSTATIN & ENDOSTATIN
The Cancer Chronicles, Spring, 1998
© May, 1998 by Ralph W. Moss,Ph.D.
The recent spate of newspaper articles and television programs about the new antiangiogenic drugs, angiostatin and endostatin, has created a tremendous amount of excitement and anxiety all over the world. The hopes of millions of cancer patients have been raised, cruelly in our opinion. We deplore the cynical manipulation of the hopes and fears of cancer patients by self-interested individuals.
Our criticism does not extend to Dr. Judah Folkman of Harvard University, discoverer of these agents. By all accounts he is ethical, determined, and brilliant. We wrote favorably about this work in "Angiostatin: A New Approach" in 1996. But while we share an appreciation for his work, we need to emphasize certain things about this current situation:
1) So far, the excellent results reported have only been in mice. It is well known that there are often outstanding results in mice that never translate into advances in the treatment of human cancer. As just one of many examples, tumor necrosis factor (TNF) also had excellent results in mice and made tumors literally fall off over night. But it has had extremely disappointing results in humans.
Similarly, when the useful drug camptothecin (derived from the Camptotheca acuminata tree) was first tested in animals it cured 36 out of 36 human tumors growing in nude (athymic) mice. However, when this same compound was put into patients the results were quite different: two "partial responses" (temporary tumor shrinkages) out of 61 patients with GI intestinal tract! (Moertel, CG, et al. Cancer Chemotherapy Report 1972;56:95.)
Many other examples could be given. It needs to be emphasized that the real test is the human, clinical situation and to date this mixture of angiostatin/endostatin has not been tried in a single human.
2) The manufacturer EntreMed does not have enough of either agent on hand to launch a clinical trial. It may be a year or more before they do and another year before the results of a Phase I-II trial would be announced. (It took almost 20 years to take TNF from the laboratory to the clinic.) Even if the Phase I-II trial was deemed positive that is not enough. It would still have to be tested in Phase III (large-scale randomized clinical trial). And even then it would probably be necessary to repeat this test at another institution, just to be sure. This could take years (presuming the company has the ability to isolate and produce this amount of these rare substances).
3) Some related products have already been tried in people, with less than startling results.
At the 1998 ASCO meeting, T. Eisen and colleagues at the Royal Marsden Trust in London reported that they gave thalidomide, an anti-angiogenic drug, to 48 patients with advanced solid tumors. These included patients with melanoma, ovarian, kidney, and breast cancer. Each recived 100 mg per day until progression. The results were that 3 of the 48 patients (6.25%) had a "differential response." Ten patients had stable disease for up to 25 weeks (with a median of 12 weeks), and 8 patients continued on the treatment. There was also an improvement in appetite and sleeping. The scientists concluded that further studies were warranted at higher doses. By all means...but this far from the "cure" that many patients believe is in the offing.
Another Phase I study has been carried out on a product called VITAXIN, which is a kind of monoclonal antibody directed against a chemical found on the blood vessels of tumor. Fifteen patients with stage IV disease were treated. They had many different types of cancer. There was one early death, which researchers ascribed to tumor progresson "and unrelated to VITAXIN therapy." Several patients developed fevers. Out of the 12 patients, there was one partial response (8.3%). Six patients appeared to have stable disease and five had progressive disease. Phase II studies are being planned. (Gutheil, JC, et al. Phase I study of Vitaxin, an anti-angiogenic humanized monoclonal antibody to vascular Integrin alpha-nu-beta-3, ASCO abstract 1998, #832.)
4) When the Phase I-II trial of Angiostatin/Endostatin is launched it is likely that around 50 patients will be treated. The Phase III trial may involve 100 or so, but half of these will have to be "randomized" to another treatment regimen, and will not receive angiostatin/endostatin. By that time there will literally be millions of people clamoring to get into this trial, and I would not be surprised if the company selects people by way of a lottery of some sort. And so one's chances of getting in will be literally like winning the sweepstakes.
5) The main appeal of Angiostatin/Endostatin is that they apparently overcome the problem of drug resistance. However, as a lead comment by Atul Gawande in the New Yorker (5/18/98) wisely pointed out (but the New York Times failed to mention), "drug resistance is just one of many factors that stymie anti-cancer drugs." Cancer in humans is a far more complex phenomenon that just the creation of new blood vessels. These are not affected by this drug. Nor does this drug combination address the multifaceted nature of cancer nor its causes. Also, angiogenesis itself is probably more complex than indicated in the newspapers, and is dependent on multiple factors in the body, such as IL-1, IL-8, bFGF, TGF-alpha, TGF-beta, PD-EGF, VPF, PAF, TNF, etc.
6) Inhibiting angiogenesis (new blood vessel formation) may not be without serious consequences or side effects. For example, angiogenesis is also present in other bodily processes, including benign diseases and normal processes as well. It is present during wound healing, ovulation, menstruation and pregnancy. It is a complex process about which we know very little. Researcher John Boik (author of Cancer and Natural Medicine) points out that "in spite of active angiogenesis, the blood supply in a solid tumor is relatively limited compaerd to that of normal tissue." In a Phase I study of SU5416, a novel angiogenesis inhibitor, various forms of toxicity were seen, including fatigue, change in voice, pain at infusion site and an allergic reaction. In rats and dogs, injury to the liver was seen (Rosen, LS, et al. UCLA School of MEdicine, 1998 ASCO abstract #843).
7) It has been known for over 100 years that tumors contain abnormally dense blood vessels networks. In the 1960s scientists realized that tumors induce their own blood supply. In 1972 Folkman and Hochberg reported that tumors implanted in the eyes of rabbits grew only to one cubic millimeter before developing their own blood supply. Antiangiogenesis was first proposed as a cancer therapy in 1971. In fact, a story about the latest work appeared in the New York Times on November 27, 1997 and was featured where it belonged, back on page A28.
This original Times article by Nicholas Wade said said what is true: these new drugs "may well prove relevant to the treatment of human cancer." Naturally, it sparked little follow-up since the same can be said about many drugs only tested in mice. Then on Sunday, May 3, 1998 basically the same story appeared on the front-page of The New York Times with the headline, "A CAUTIOUS AWE GREETS DRUGS THAT ERADICATE TUMORS IN MICE." As the New Yorker said, however, "the article...was longer on awe than on caution. A media frenzy ensued." It turns out that the author of the second article, science reporter Gina Kolata, had sat next to a famous scientist, James Watson, at a dinner party, where he regaled her with extravagant praise of Judah Folkman, such as "Judah is going to cure cancer in two years." It was an unguarded moment of overenthusiasm. You should also understand that cancer drug development is not Dr. Watson's field.