NEWS

Tyrosine Kinase Inhibitor Research Presses on Despite Halted Clinical Trial

Ken Garber

Successful drugs make headlines, but the failures quietly disappear from view. One experimental drug highly touted at previous American Association for Cancer Research meetings, Sugen Inc.’s SU-101, was notably absent from this year’s poster sessions. But in hallways and hotel rooms, news of the drug’s fate quickly spread by word of mouth: the South San Francisco-based biotech company had terminated the phase III clinical trial. Another cancer drug had failed.

The news was especially disturbing, since SU-101 was in the vanguard of a class of drugs known as tyrosine kinase inhibitors. These agents have captivated oncologists because they are precisely targeted at cancer abnormalities and should be relatively nontoxic. And drug companies have embraced them with unprecedented eagerness: at least 18 tyrosine kinase inhibitors are in the clinic and scores are in preclinical development. Because SU-101 was the closest to FDA approval, its demise sent a shudder through the vast community of researchers working on these drugs.

But SU-101’s fate "isn’t a showstopper for the entire field," stressed Paul Workman, Ph.D., director of the Cancer Research Campaign Centre for Cancer Therapeutics in Surrey, England. "It simply means that particular molecule wasn’t right." SU-101 had obvious problems, related to its tendency to be metabolized (and inactivated) quickly in the body, that were reported 2 years ago. So the field is likely to continue its forward surge with other agents that could become a breakthrough drug.



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Dr. Paul Workman

 
Enzymes and Oncogenes

Whichever tyrosine kinase inhibitor first wins marketing approval, it will be the culmination of a story that began 25 years ago, when tyrosine kinases—enzymes that can also be oncogenic—were first implicated in human cancer. The first oncogene, src, produced a tyrosine kinase. Its 1975 discovery by Harold Varmus, M.D., and Michael Bishop, M.D., was an early triumph of gene-based cancer research. Knowing that the src gene of the Rous sarcoma virus caused cancer in chickens, Varmus and Bishop first thought a similar gene in the chicken genome had been acquired from an ancient virus. But the reverse proved to be true: src was present in every vertebrate genome, and therefore must have come first. Hence, it was the original oncogene, and its discovery earned Bishop and Varmus the 1989 Nobel Prize.

In 1980 the Salk Institute’s Tony Hunter, Ph.D., and Jonathan Cooper, Ph.D., showed that Src protein phosphorylates—that is, donates a phosphate group to—the amino acid tyrosine on its target proteins. So Hunter and Cooper called Src a "tyrosine kinase." Seven more tyrosine kinases, including erbB2 and endothelial growth factor, were found and cloned in the early 1980s at Genentech Inc., San Francisco. Several hundred are now thought to exist, and many have the potential to cause cancer.

In the 1980s and early 1990s, many researchers scoffed at the idea of making drugs targeting tyrosine kinases. Although early drugs worked in the laboratory dish, "the thought was, you get into animals and all these things would be impossible," recalls Edward Sausville, M.D., Ph.D., associate director of the National Cancer Institute’s Developmental Therapeutics Program. One concern: these drugs work by blocking the adenosine triphosphate binding site of the kinase. Many "normal" enzymes also use ATP, so the drugs seemed likely to cause serious side effects by shutting down much normal biology.



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Dr. Edward Sausville

 
The worries now seem vastly overblown. "Fortunately the pioneers have forged ahead and we have inhibitors coming through, and the concerns are beginning to disappear," said Workman. Animal trials (and some human trials) have been encouraging. One outstanding example: Novartis’s STI-571, for chronic myelogenous leukemia (see News, Jan. 5, p. 6). "You can get selective kinase inhibitors," said Workman.

But skepticism remains. Experiments by Peter Houghton, Ph.D., of St. Jude Children’s Research Hospital, Memphis, Tenn., and others show that the drug concentration necessary to block tumors is much higher than needed to shut down the target signaling pathway, suggesting that the drugs are also working through other unknown pathways. Such uncertainty is worrisome, Sausville said. As human trials begin, he said, "we just need to go into it with our eyes open," methodically testing which signaling pathways the drugs block.

Quick Metabolism

SU-101 targeted the platelet-derived growth factor (PDGF) signaling pathway, which is involved in many cancers. But the body quickly converts SU-101 to a metabolite that does something completely different. The parent compound’s short life may be the reason SU-101 proved no better than procarbazine, a chemotherapy drug, for relapsed patients with glioblastoma multiforme, a viciously aggressive brain tumor.

"We still do not understand how 101 works" on a molecular level, said Laura Shawver, Ph.D., Sugen’s vice president for preclinical and pharmaceutical development. "So we just are stepping back a little bit to evaluate how best to go with that compound."

SU-101’s failure in the clinic is a warning for other tyrosine kinase inhibitors, but not a death knell. "Because of these other [metabolite] issues, it shouldn’t be regarded as meaning anything one way or another for the field," Sausville said.

Sugen, the company that pioneered the field, has shrugged off the demise of its lead compound. Last year Pharmacia acquired Sugen, leaving it largely intact. Most of its senior managers have stayed on, eager to show proof of principle in the clinic. With SU-101 stalled, hopes now fall on two other drugs, SU-5416 and SU-6668 (see News, April 5, p. 520). SU-5416 (now in phase III trials for colorectal cancer) is an angiogenesis inhibitor that targets the VEGF receptor, Flk-1. SU-6668 (in phase I) is a broader-acting version that is designed to block activity of Flk-1 and two other tyrosine kinases. "We’re certainly excited about the data," said Shawver. "There’s a lot of optimism."

While broader-acting drugs run a greater risk of side effects, most companies favor them. A big worry is that patients will develop resistance to drugs that are too narrowly targeted. "Tumors are generally driven by four or five or six abnormalities," Workman pointed out. "Taking any one of those out, will that give you enough of an antitumor effect, or will the other abnormalities simply take over?"

Workman isn’t sure. "What most likely will happen is that resistance will develop due to those other [genetic] abnormalities coming through," he said.

AstraZeneca’s ZD1839 targets a single kinase—the EGF receptor—and it runs the risk of tumor resistance. Still, the EGF receptor is a promising target for two reasons: it is found in many tumors, including breast, ovarian, renal, and lung; and its overexpression (like erbB2) often means a highly aggressive cancer. AstraZeneca has jumped ZD1839 from phase I studies straight to phase III, which began in May. The effort has been low-key.

AstraZeneca will be giving lung cancer patients either ZD1839 plus chemotherapy or chemotherapy alone. "You don’t throw away good existing treatment," said George Blackledge, M.D., Ph.D., AstraZeneca’s medical director of oncology. "You add great drugs to existing treatment." Most cytostatic drugs will probably be used in such combinations, since cytostatic drugs block a tumor’s ability to grow but might not kill existing tumor cells. "If patients survive longer and you have better quality of life, even though you haven’t got totally rid of the cytotoxic drug, that’s perfectly fine," said Workman.

And patients, once on these drugs, may never go off. Lifetime use seems warranted to keep cancer from recurring. That alluring prospect is driving the enormous drug company development effort: profit potential from such pills, if they can be made safe enough, is enormous. Unlike many cancer therapies, "companies perceive this as a market," Sausville noted. It’ll take a lot of failures like SU-101 to change that reality. Profit incentive is a good thing, Workman said. "If we can convince companies that they should be working in the cancer area," he said, "then it’s a win-win."


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