At the Ireland Cancer Centera part of University Hospitals in Cleveland, OhioScot Remick, M.D., was proud to have his developmental therapeutics program be the first chosen for a clinical trial of combretastatin, an angiogenesis inhibitor made from the bark of a South African species of willow tree.
But because the trial, which opened in late 1998, would be a phase I study that by definition would focus on safety concerns, he did not expect that "partial responses, let alone a complete remission" would come out of it. "Its really been extraordinary," he said. "Clayton Twigg is truly our poster boy."
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The Twigg story, of course, could well prove to be just a flash in the pan, although there have been other patients in Remicks phase I combretastatin study whose previously very aggressive cancerssome of them metastaticstabilized after treatment for 24 weeks or more. Without the benefit of more extensive clinical trials, it is hard to tell how this drug will ultimately fare. Indeed, the same goes for all of the drugs contending for places in the antiangiogenesis sun.
The license for the systemic use of combretastatin was originally held by Oxigene Inc., of Boston, Mass., which recently sold it to Bristol-Myers Squibb.
There are many antiangiogenesis contenders out thereat least 20 are in or soon to be in clinical trials. Moreover, the list of contenders is growing. In the first 6 weeks of 2000 alone, a single companyEntreMed Inc., Rockville, Md., which made news last year when human testing of endostatin began under its auspicesannounced that the U.S. Food and Drug Administration has given it permission to launch phase I trials of angiostatin and 2-methoxyestradiol (2ME2) as well.
Angiostatin, like endostatin, is a protein discovered in the laboratory of antiangiogenesis pioneer Judah Folkman, M.D., at Childrens Hospital Medical Center in Boston. The antiangiogenic effects of 2ME2 were discovered in Folkmans lab as well, but the drug differs from angiostatin and endostatin in that it is not a protein; it is a natural metabolite of estrogen.
Although preclinical studies of 2ME2 showed it to be active against an array of cancers, only advanced breast cancer patients will be enrolled in its initial phase I trial, which will open soon at the Indiana University Cancer Center in Indianapolis. Thomas Jefferson University Hospital in Philadelphia will open the first phase I trial of angiostatin.
Matrix Breakdown
So what does it take to track developments in this field? For openers, it helps to know that angiogenesis is the formation of new blood vessels from the endothelial cells that line old vessels. The formation of these vessels is needed to provide tumors with oxygen and nutrients. While angiogenesis is routine during the menstrual cycle, pregnancy, and gestation and also during wound healing, it is otherwise rare because a balance between regulatory factors that encourage angiogenesis and those that discourage it ordinarily keeps these cells in a steady state. The crux of the antiangiogenesis strategy for cancer treatment, therefore, is to restore or maintain that equilibrium.
Nonetheless, angiogenesis is not a single event, but the culmination of a cascade of events. That being the case, there are multiple opportunitiespotentially at leastto disrupt the process, and virtually all the drugs currently in clinical trials or being readied for them reflect this fact.
For angiogenesis to occur, for example, there must first be a breakdown of the supportive materialcalled the matrixthat ordinarily serves as a barrier to endothelial cells sending out new shoots. Matrix metalloproteinases (MMPs) are enzymes that facilitate that breakdown. The thinking, accordingly, is that drugs that inactivate MMPs may nip the process in the bud. At last count, five such drugs were being deployed (either singly or in combination with other therapies) against several cancers, including pancreatic, lung, breast, and hormone refractory prostate cancers, in one or another phase I, II, or III clinical trial.
Other investigational drugs either act on endothelial cells directly to deter them from forming new blood vessels or, like MMP blockers, do that indirectly in some way. Angiostatin and endostatin are examples of the first sort of drugs, and combretastatin has been added to the list. Unlike angiostatin and endostatin, however, it takes aim at existing blood vessels in tumors rather than preventing the formation of new ones.
Delivery Methods
Still, it is sometimes not just how well an angiogenesis inhibitor performs in preclinical studies but also how it can be given that makes it of interest. IM862, a small (twoamino acid) peptide, made by Cytran Inc., Kirkland, Wash., is an example.
Parkash Gill, M.D., of the University of Southern California, Los Angeles, conducted a trial of the drug in 30 patients with AIDS-related Kaposis sarcoma who had poor responses to other measures. He told the December angiogenesis meeting that "about a third" had benefitted from the peptide, some of them "dramatically" and described the improvement as "durable." Also in the molecules favor, he reported, is that it is absorbed into the bloodstream across mucosal surfaces and so is administered in nose-drop form. (Gill also reported that phase I trials of IM-862 for melanoma and recurrent ovarian cancer are under way.)
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The work in question was done with interferon, but Fidler believes the principle will likely be more broadly applicable. "The paradigm has to shift from searching for cures for cancer to making it into a disease that can safely be managed with the chronic administration of drugs that have little or no toxicity," he said. "That means that clinical trials (of drugs with antiangiogenic potential) are going to have to change; they are going to have to be correctly designed."
Fidler also questions a frequently heard prediction: that angiogenesis inhibitors that tame one kind of cancer will probably also tame most of the rest, including not only solid tumors, but many lymphomas and leukemias as well.
"You have to remember that the endothelial cells (lining the blood vessels) of different organs are phenotypically different," Fidler said. "Some of these agents, therefore, may be active in some organs, but not others. We may have to learn how to tailor our antiangiogenic therapy to that reality."
Nonetheless, Fidler is clearly excited by prospects for that therapy. "Unlike many earlier strategies, its solidly based on biology, not on wishful thinking," he said. "Thats so wonderful."
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