By David N. Leff
Living with cancer, rather than dying of it, is the take-home concept of a stubby molecule reported Tuesday to the American Association For Cancer Research (AACR) at its 90th annual meeting, in Philadelphia.
An afternoon poster discussion session on tumor invasion heard a report titled ¿An 8-mer peptide derived from the non-receptor binding region of urokinase plasminogen activator inhibits breast cancer growth and metastasis through the induction of apoptosis in vivo.¿
Its presenting author was tumor biologist and clinical oncologist Shafaat Rabbani, of McGill University in Montreal. His co-presenter, medicinal chemist Terence Jones, is chairman and CEO of Engstrom Pharmaceuticals Inc., of San Diego. His firm synthesized the proprietary peptide, E6 by name, used in the in vivo breast cancer trial they reported. (See BioWorld Today, March 18, 1999, p. 1.)
¿The interesting thing about this E6 molecule,¿ Rabbani told BioWorld Today prior to his presentation, ¿is that it is a derivative of the urokinase plasminogen activator, which we refer to as uPA. For years, studies have reported the correlation between urokinase, a serine protease, with tumor progression. It has been seen at high levels as a prognostic marker in common cancers, such as breast, prostate and colon tumors.
¿Engstrom synthesized this peptide,¿ Rabbani continued, ¿based on the actual sequence of urokinase. We assayed it first in vitro for its ability to block tumor cell invasion. We then went on to test it in tumor-carrying rats and mice, in both of which it blocked not only tumors but also their metastases.¿
Jones observed, ¿We chopped E6 out of the uPA sequence. It is a very short peptide, just 8 amino acid residues long. So we can make it very readily either by the gram, or eventually by the kilogram. Also, it¿s very water-soluble.
¿We know,¿ he pointed out, ¿that E6 interferes indirectly with the association of uPA to its cell-surface urokinase plasminogen activator receptor ¿ uPAR. When uPA binds to this receptor, highly important invasive effects take place. E6 prevents that association, and switches off those invasive manifestations. That¿s what it¿s actually doing, in mechanistic terms.¿
Then, in preclinical in vivo terms, Rabbani related the peptide¿s effects on tumor growth and metastases:
¿In the case of human breast cancer,¿ he said, ¿we implanted those tumor-cell xenografts into the mammary fat pads of female nude mice. Then we injected this E6 peptide twice daily over a period of six weeks systemically into their peritoneums. At that endpoint we got to see greater than 90 percent reduction in tumor growth, and more than 80 percent reduction in metastasis to the lymph nodes. This is the best result we have ever seen in this particular system, especially in the case of urokinase-mediated effects.¿
The presenters¿ abstract included a chart reflecting the tumor-growth differences between the treated mice and control animals. For the first three weeks, neither cohort displayed significant changes. Then growth in the controls took off, and zoomed to more than 270 cubic millimeters of tumor volume. During that same period, tumors in treated mice expanded to a scant 20 cubic millimeters.
In rats, inoculated with rat-strain tumor cells, E6 continued to suppress their growth throughout the treatment period. ¿We are very much encouraged,¿ Rabbani recalled. ¿This peptide is exciting stuff,¿ he added, ¿because one can give it, and we don¿t see any side effects, no visible toxicity, with this small compound.¿
¿The good thing about it,¿ Jones pointed out, ¿is that E6 is almost a small molecule. We intend to turn it into a very small peptidomimetic, which will be orally available. That¿s our ultimate goal.¿
Meanwhile, he said, ¿We are talking with several multinational pharmaceutical companies and Japanese firms about their out-licensing of this project.¿
Based on these findings, Jones then laid out his rationale for reforming cancer from a death sentence to a long-term manageable disease.
¿What we are doing,¿ he began, ¿is coming forth with non-toxic, chronic treatments of metastases. The surgeon can deal very effectively with a primary tumor. But all tumors are metastatic.¿ To support that statement, he cited Judah Folkman, a founding father of anti-angiogenesis. ¿Folkman said that a tumor cannot grow beyond the size of a rice grain without pulling in its blood supply.
¿It¿s also true,¿ Jones observed, ¿that there¿s no method of clinically detecting a tumor smaller than the size of a little olive or grape.¿
To develop his argument, the Engstrom executive proposed this syllogism: ¿Angiogenesis is the root cause of metastasis: If tumors can¿t grow beyond the size of a rice grain without angiogenesis, if angiogenesis causes metastases, and if a tumor cannot be detected until it¿s the size of a small olive, then in every case a detected tumor must be metastatic at diagnosis.¿
It¿s The Metastases, Stupid
¿Those metastatic seeds may die on the journey out from the primary,¿ Jones observed, ¿and get immunologically recognized and ablated. Chemotherapy and radiation try to systemically destroy the metastases, but quite often don¿t. And then you get Darwinian evolution of resistant clones, which defy all drugs. At that point the patient is terminal.¿
Jones¿ alternative it to ¿go after these little metastases with chronic, nontoxic, uPAR-blocking therapy. We will treat cancer as a manageable disease. We will teach patients to live with their metastases for many a year. Patients will readily accept that situation as long as the drug is nontoxic. And we know that in E6 there are no detectable side effects.
¿As long as these metastases stay tiny they¿re effectively not there at all. And cancer,¿ Jones concluded, ¿is not a big C¿ in this philosophy. It¿s a little C.¿¿