Every organ in the body develops its own type of cancer, but thesevaried solid tumors all share the same Achilles heel _ the need for ablood supply to feed their malignant growth and metastases, whileremoving wastes.
A way to exploit this common denominator of cancer is on thedrawing boards at the Scripps Research Institute in La Jolla, Calif.,and its commercial partner, Ixsys Inc., of San Diego.
The name of the game that tumors play to spawn their privatenetwork of venules, arterioles and capillaries is angiogenesis. Cuttingoff this spreading pipeline at the pass is the strategy that Scrippsmolecular cell biologist David Cheresh and his co-workers have nowbrought to a point where they nipped half a dozen assorted humancarcinomas in the bud, ending their careers as burgeoning solidtumors.
A paper in the current issue of Cell, dated Dec. 30, describes theirfeat, and its clinical potential. Its title: "Integrin avb3 antagonistspromote tumor regression by inducing apoptosis of angiogenic bloodvessels."
To be sure, their anti-angiogenesis, anti-cancer experiment waspreclinical. Not in vitro or in vivo, but in ovo, it played itself out onthe eggs of chick embryos, seeded with minute fragments of humancolon, lung, breast, larynx, pancreas and melanoma tumor tissues.
"What we've shown in this Cell paper," said Cheresh, its seniorauthor, "is that when we introduce an antibody into the bloodstreamof chick embryos with human tumors, we can selectively shut offblood vessels going to the tumor. And more important," he toldBioWorld Today, "we can block or actually cause regression of thosetumors."
Integrins Wear Two Hats
Cheresh added, "Virtually every tumor that we've placed in thiseggshell model has shown a factually complete regression, after asingle vascular injection of either our LM609 monoclonal antibodyor a small synthetic peptide. Both of them antagonize the a vb3integrin receptor molecule."
Integrins are a family of cell-adhesion receptors involved in a widevariety of biological events. This particular integrin, avb3, promotesthe sprouting of new blood vessels, whether to grow tumors, gestateembryos, heal wounds or provide for female menses. The Scrippsgroup had reported earlier that the avb3 integrin receptor showed afourfold increase in expression during angiogenesis on the chickchorioallantoic membrane, the translucent pellicle that lies justbeneath the egg shell.
This membrane crosses the broad end of the shell, leaving a gap thatgives an emerging chick its first breath of air. In Cheresh'sexperiment, he opened a pseudo-air sac at the opposite end of theegg, carved away the outer shell to create a centimeter-squarewindow, and planted tumor fragments on the exposed membranesurface.
"If you wait till day 10 when you start to do that," Cheresh said,"you selectively shut off new vessel growth without affecting thepreexisting vessels."
The gestating chick's own blood-vessel network, (visible by holdingany fertilized hen's egg up to the light), soon started sending outbranches to feed those blood-thirsty malignancies via angiogenesis.Enter the Scripps antibody and peptide antagonists to that integrinreceptor.
Twenty-four hours later, the chicks received intravenous injectionsof either the anti-avb3 LM609 monoclonal, or an irrelevant controlantibody, or a simple saline solution. Then they were allowed topropagate for another six days.
Result? To quote Cell: "Tumors treated with [saline placebo orcontrol antibody] proliferated in all cases. In contrast, themonoclonal antibody LM609 not only prevented the growth of thesetumors but induced extensive regression in most cases.
"Embryos examined after seven days of tumor growth [embryonicday 17] appeared normal upon gross examination, whether or notthey were treated with an avb3 antagonist. The researchers drew theconclusion from these findings "that antagonists of this integrinappear non-toxic."
The acknowledged father of tumor angiogenesis research is JudahFolkman, who holds an endowed chair at Harvard Medical School.He acclaimed the Scripps results in these terms: "To be able toinduce tumor regression by turning off neovascularization to thetumor with such specificity that there is no toxicity to normal cells isa remarkable achievement."
Driving Tumors To Suicide
Besides the LM609 monoclonal antibody, Cheresh had anotherstring to his angiogenesis-blocking bow. This is a small cyclicpeptide, synthesized for Scripps by E. Merck, of Darmstadt,Germany, which manufactures reagents and biotechnology researchproducts. "That cyclic peptide," Cheresh said, "has the same effect asLM609."
In March 1993, Cheresh and his post-doctoral co-inventor, Peter Brooks, applied for a U.S. patent covering theinhibition of angiogenesis by antibodies, peptides or mimetics thatcould block the function of the selective avb3 integrin.
E. Merck has licensed the Scripps patent to develop peptides andsmall compounds as antagonists to avb3, for inhibiting angiogenesis.
And Ixsys has licensed the LM609 monoclonal. In collaboration withCheresh and his group, Ixsys will apply a humanized version of theantibody for anti-tumor therapeutics. Biochemist Judith Varner, whomanages the company's angiogenesis program, told BioWorldToday: "Our goal is to enter clinical trials in 1996. We applied aproprietary technology to humanize the antibody, and currently wehave expressed it as a full-length immunoglobulin G-1, which wetrademarked Vitaxin. Currently, we have it in the production phase,with the goal of filing an IND [investigational new drug] applicationwith the FDA by the end of this year."
She said that "the potential for commercialization is vast. There areat least 600,000 new cases of cancer a year _ solid-tumor cancer _in the U.S. And we currently believe that this technology can beapplied to all of them." Expanding on Cheresh's rationale, Varnerexplained, "Every solid tumor is characterized by its own bloodsupply. That is probably the one and only really commondenominator of solid-tumor cancers." (See BioWorld Today, Sept. 9,1994, p. 1.)
Noting that the FDA "will currently allow clinical trials only inpatients who have failed other treatments," Varner said, Ixsys is nowtrying to identify the tumor types for its initial human studies. "Theywould include breast cancer, prostate, brain cancer, melanoma andKaposi's sarcoma.
Ixsys is currently seeking a corporate partner for developing itsVitaxin LM609 anti-angiogenesis monoclonal antibody for theclinical trials beyond the Phase I studies, which it will manage itself.
Meanwhile, Cheresh's lab is moving up from in ovo to in vivo. Theyhave transplanted human tumors into human neonatal foreskinengrafted onto severe combined immune deficiency disease mice."Preliminary data," Cheresh said, "says that we can blockangiogenesis in response to the human tumor."
He explained: "The transplanted neonatal tissue has human bloodvessels in it, which connect up with the mouse's blood vessels. Thenwe can introduce a human tumor-cell population into the rodent'sdermis. The tumors will grow, and attract a human blood supply."
A tail-vein antibody injection, he said, would then shut down tumorgrowth in that model.
Cheresh concluded: "Initial results in these mice are extremelyencouraging. They appear to support in vivo what we reported inovo." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.