Not since the interferon craze of the early 1980s has a cancer drug captured the public imagination like Novartiss STI571. Under the trade name GleevecTM, it won approval from the U.S. Food and Drug Administration on May 10 for treating chronic myeloid leukemia after a lightning-fast 2 1/2-month review (see sidebar, p. 972).
Network TV special reports and a Time cover story trumpeted the drug. American Society of Clinical Oncology President Larry Norton, M.D., in the New York Times, called STI571 "the beginning of a sea changeand I am speaking conservativelyin the way we practice medicine."
The drug is amazingly effective: In a phase I trial, 98% of patients with chronic myeloid leukemia achieved a complete hematologic response, and phase II results have been almost as stunning. But only about 4,500 people in the United States develop CML each year. The burning question: Will more common cancers respond to targeted drugs like STI571, or is STI571 for CML a one-time-only success?
The main reason for doubt is that CML is caused by a single genetic abnormalitythe Philadelphia chromosome translocation that generates the Bcr-Abl fusion protein. While targeting Bcr-Abl with STI571 is effective, more common cancers typically involve many genetic hits, driving multiple abnormalities that contribute to uncontrolled cell growth.
So it is possible that separate drugs will be needed against each abnormality and will need to be used in the right combination. Such complex therapies could take decades to develop. Do drugs in the pipeline have any hope of working well against breast cancer, prostate cancer, lung cancer, and colon cancer?
"I would say that answer is yes, with a qualification," said Charles Sawyers, M.D., of the Jonsson Comprehensive Cancer Center at the University of California at Los Angeles. First, Sawyers said, we must identify the signaling pathways driving individual cancers. "There will be five or more different kinds of prostate cancer," he predicted, "each driven by a different signaling pathway or genetic event."
For example, EGFepidermal growth factoris a receptor tyrosine kinase implicated in many common cancers such as breast and prostate cancers. "A good drug against an EGF receptor would probably have a great response rateif you could identify the right patients," he said. Several EGF receptor inhibitors are now finishing phase III clinical trials.
Sawyers argued that researchers must start molecularly typing individual cancers immediately to better predict which patients will respond to various drugs. "I think everybody knows this, they just dont admit it," he said. Herceptin, for example, is usually only given to breast cancer patients whose tumors demonstrate (by immunohistochemical stain) overexpression of the Her2/neu receptor.
But more than overexpression drives other kinases. The EGF system, for example, also involves heterodimerization, receptor mutations, and autocrine/paracrine activation by multiple ligands. Predicting who will respond to the EGF-targeted drugs, especially in combination therapy, "is going to take a lot longer clinical experience," said Nick Lydon, Ph.D., vice president of small molecule drug discovery at Amgen Inc., Thousand Oaks, Calif.
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Some clinical oncologists are making a start. Charles Blanke, M.D., of Oregon Health Sciences University, Portland, reported dramatic results at the recent ASCO annual meeting of a phase II study in which patients with gastrointestinal stromal tumors (GIST), rare but extremely aggressive solid tumors, were treated with STI571. The overall response rate was a stunning 59%, with durable responses.
Blanke individually typed many patients for mutations in the gene for c-Kit, the tyrosine kinase that drives GIST. "Activating mutations in exon 11 strongly predicted for response [to STI571]," he reported.
However, gathering such information is labor-intensive and could involve multiple tumor biopsies, so it is not usually done, said Sawyers. But, he stressed, it should be. "I dont know if we should be preaching to the oncology crowd or to the pharmaceutical development people wearing suits and hanging out in northern New Jersey," Sawyers said. "If oncologists say [to drug companies], Youve got to do it this way, theyll do it that way."
Questions Remain
Even if drug companies come on board, reliable markers are identified, and predictive assays are developed, there is no guarantee that the next wave of signal transduction inhibitors will work well. Even STI571 has limitations. Researchers do not know if the drug slows progression of CML from chronic phase to blast crisis, the diseases grim end stage when leukemic cells overwhelm the body and fatal hemorrhage, clotting, or infection invariably follows.
Patients in blast crisis receiving the drug show an excellent 52% overall response rate, but most of the responses do not last. That is because, as CML progresses, "there is an increase in what people have called the genetic plasticity of the tumor," explained Edward Sausville, M.D., Ph.D., associate director of the National Cancer Institutes Developmental Therapeutics Program. "With the increase in genetic plasticity come additional changes that then render the disease more difficult to treat."
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But, for other cancers, details of genetic instability remain a mystery. "What is the basis of genetic plasticity?" asked Sausville. "How can we influence the rate at which additional changes occur? ... Even if you can diagnose which [signaling] pathways are active [in a given cancer], youre going to have to cut down on the rate at which a given cell acquires many changes."
Sausville said he thinks that new therapies that solve the resistance problem must wait for advances in basic science to provide answers. Then, "hopefully, ways of interdicting or altering that process will make themselves apparent," he said.
In the meantime, should we lower expectations for STI571s successors now working through the pipeline? Many of them will be effective, believes Sara Courtneidge, Ph.D., deputy director of the Van Andel Research Institute, Grand Rapids, Mich., but perhaps not as single agents. "I dont think anybody thinks were going to get oncologists to throw away everything thats in their black bags and simply use a signal transduction inhibitor," she said. "The future is in combining these therapies with conventional chemotherapy."
Sausville, for his part, does not rule out more noncytotoxic successes like STI571. "The problem is going to be to define what the best cocktail of signaling agents [is] for a particular patients tumor," he said.
About two dozen signal transduction inhibitors are now in clinical development, with many more in the pipeline. Those furthest along attack targets that were identified, cloned, and validated back in the 1980s: the EGF receptor, vascular endothelial growth factor, platelet-derived growth factor, and protein kinase C. Several phase III trials are now complete or close to completion, so the efficacy (or lack of efficacy) for highly touted drugs like Astra-Zenecas ZD1839 (IressaTM) and OSI Pharmaceuticals OSI-774 (TarcevaTM) should soon be known.
Drug companies, in general, are now shifting attention from cell surface receptors like EGF to kinases in the cytoplasm and nucleus. Wyeth-Ayerst, for example, has an mTOR inhibitor, CCI-779, in phase II trials. Sawyers calls the mTOR kinase "very promising." Amgens Lydon favors Akt, a kinase that is part of the antiapoptosis pathway. Pfizers CI-1040 targets MEK, a key player in the MAP kinase pathway that is overactivated in many common cancers. Drugs targeting the cyclin-dependent kinase pathway (which regulates the cell cycle), like Kyowa Hakkos UCN-01, also are entering the clinic.
So is STI571 the beginning or the end? "Definitely, its the beginning," said Lydon, who led the team that developed the drug at Ciba-Geigy a decade ago. Doctors testing the next crop of drugs are eagerly watching for effects like STI571s.
"When we were first doing the phase I trial, we saw that all the white counts started coming down once we got to the right dose," Sawyers recalled. "We were just amazed. We were just so ecstatic." Sawyers, for over a decade, had been treating CML patients in blast crisisand watching them die. Then STI571 changed everything. "Its gratifying, it really is," he said. "Sometimes I kind of wonder if its really true."
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