Sniffing Out the Promise of Anti-Angiogenesis Therapy

A team of University of Southern California (Los Angeles) scientists led by Parkash Gill have shown in a human clinical trial that a small peptide, in the form of a nose drop, may be a successful anti-angiogenesis treatment.

Gill's data on the anti-angiogenesis peptide IM862 in the treatment of Kaposi's Sarcoma (KS) was presented at the annual meeting of the American Society of Clinical Oncology this past week and was featured in a press conference on novel cancer therapies on Sunday, May 16.

In Phase II of the clinical trial of IM862, from which the data presented were taken, Gill and coworkers treated 35 patients with an intranasal solution administered as a nose drop of IM862. Thirty-seven percent of the patients showed a major response, defined as either complete resolution of the KS lesions (4 patients) or partial reduction in tumor size (9 patients) within six weeks of beginning treatment. In another 17 patients, the disease has not progressed for six months or longer.

"All this occurred with very few side effects," says Gill, "mostly mild headaches."

IM862—now well into Phase III clinical trials—is among the first anti-angiogenesis drugs to get to this phase all on its own, says Gill. "Most of the other anti-angiogenic drugs are combined with chemotherapy," he notes. "This may end up being the way this family of drugs will be developed." The drugs that started the anti-angiogenesis excitement last year, angiostatin and endostatin, have not yet reached Phase I trials.

IM862, a thymic dipeptide, was developed by Cytran Inc., a private held company located in Kirkland, WA. It does not go after tumor cells directly—in fact, says Gill, "it is not cytotoxic to any tumor cells." Instead, IM862 inhibits blood vessel formation. Curiously, it also modulates the immune system.

KS is treatable (though not curable) with conventional chemotherapy, but, notes Gill, "chemotherapy comes along with so much toxicity that people will only stay on it for a period of time before they literally get sick of it." IM862, on the other hand, may be taken for a prolonged period of time if the tumors' response remains positive.

In addition to being safe, IM862 is a small molecule that makes synthesis and production of the peptide fairly simple. Its size also makes nasal administration possible, since the drug gets past the nasal membrane intact, so that more than 70% of the given dose winds up in the bloodstream. Because the peptide is destroyed by the stomach, it can't be put into pill form, says Gill.

"Unlike many other cancer drugs that must be given by injection, this peptide can be self administered by the patient as a nose drop," says Gill.

Perhaps an intriguing thing about anti-angiogenesis drugs like IM862 is that they work indirectly by altering the function of other cells. For example, the drug seems to interact with a number of different immune system cells once it has made its way into the body. The peptide appears to stimulate natural killer (NK) cells by enhancing production of the cytokine interleukin-12.

This immune stimulation, potent on its own, also has an anti-angiogenic effect, Gill notes. "NK cells produce factors which are toxic to endothelial cells," he explains. Endothelial cells are the cells out of which blood vessels are made, and from which KS and other tumors develop.

But IM862's effect on blood vessel formation reaches even further. Gill and his colleagues found that when chicken allantoic membrane was exposed to IM862 (the vessel-rich embryonic membrane is a standard tool for testing anti-angiogenic activity), blood vessel formation was blocked. Later they found that the blood vessel count in tumors implanted in mice was reduced when the tumor was treated with IM862.

Its main effect, says Gill, appears to be in reducing production of vascular endothelial growth factors, or VEGFs, and blocking the function of BFGF, which Gill says are "major mediators of angiogenesis, tumor growth and spread. These growth factors are produced by tumors and the stroma around tumors."

Perhaps the most intriguing aspect of IM862 is that it performs its magic long-term relative to its biological half-life, which is all of five minutes. "Obviously, that's too short a timespan for it to do anything directly," says Gill. "That's why we need to consider the secondary effects it causes: the decrease in VEGF production, the increase in IL12 production, the stimulation of natural killer cells and their products."

One of IM862's secondary effects is on monocytes, white blood cells that are the precursors of macrophages. On its own the drug cannot make a dent on the proliferation of endothelial cells. Add monocytes into the mix, however, and the peptide begins to make its presence known to the immune system. Monocytes (immune cells that eventually develop into macrophages) secrete a number of growth factors, and hence have a significant role in blood vessel formation. When a monocyte's chemical secretions are treated with IM862, the potency of the growth factors is reduced. "IM862-treated supernatants reduce endothelial cell proliferation by two-thirds," says Gill. "For patients with KS—and potentially a host of other cancers—that's all you need to reduce or even obliterate the disease."

Studies looking at IM862's efficacy in treating ovarian carcinoma and melanoma are also ongoing, and studies of other cancers are planned.

"The initial idea of anti-angiogenesis therapy was to stop tumor growth and spread," says Gill, "but in the lab, we and others have seen that newly-formed vessels are susceptible to actual cell death if we deprive them of certain factors. That leads us to think that if we can destroy newly formed vessels, the cells dependent on them for their supply of nutrients will also die. And that is certainly what seems to be happening here."

For more information: Parkash Gill, Associate Professor, Division of Hematology, USC/Norris Comprehensive Cancer Center and Hospital, 1441 Eastlake Ave., Los Angeles, CA 90033. Tel: 323-865-3809. Email: parkashg@hsc.usc.edu.

By Angelo DePalma