Slowly but Surely, Turning Science into Medicine
The theme of this year's ASCO annual meeting was "Translating Research into Practice." The phrase is open to interpretation, but many would agree that translation is an art, not a science, and that it usually takes a long time.
Consider the example of Met, a gene discovered at NCI in the early 1980s. Two decades later, the gene has emerged as an important player in a variety of cancers, including lung, gastric, and melanoma. Many companies are developing drugs to block signals from the Met protein, which can drive cells to grow and spread.
Whether any of these drugs will be safe and effective is an open question. But studying Met has led to new insights into how cells communicate and what can go wrong in cancer, making it a model for developing targeted therapies.
At the meeting, many researchers got their first look at clinical results for Met inhibitors. The news was positive. Two drugs - one developed by ArQule (called ARQ 197) and another by Exelixis (called XL880) - may have benefited some patients and were well tolerated.
"These are two interesting novel agents and both have encouraging antitumor activity," said Dr. Francisco Esteva of the University of Texas M. D. Anderson Cancer Center, who discussed the presentations at the meeting.
Each drug was tested against multiple cancers, and the drugs themselves were different: ARQ 197 inhibits Met alone, while XL880 inhibits Met and another signaling protein, VEGFR2.
Met plays an important role in early development. But the gene is less active later in life, and this helps make it an attractive therapeutic target.
In one XL880 trial, several patients with papillary renal cell cancer appeared to respond. This disease is difficult to treat and can occur because Met is mutated or amplified (extra copies of the gene are present in a cell).
The results are "exciting," said Dr. George Vande Woude, whose laboratory at NCI discovered Met and led the early work on the gene. "This is some of the first evidence that the strategy of inhibiting Met is working in the clinic."
Dr. Vande Woude now directs the Van Andel Research Institute in Grand Rapids, MI, which maintains an online database of studies on Met (technically called c-Met) and cancer. Collectively, the studies tell the story of Met research and provide an indication of how much time and money may be required to take a discovery from the laboratory to the clinic.
"Translation takes time, and there is no shortcut," commented Dr. Vande Woude. He noted that work on trastuzumab (Herceptin), one of the successful new targeted drugs, began shortly before Met was discovered.
For many years, drug developers thought that inhibiting Met might affect the liver or other organs, but research eventually allayed these concerns. "Various groups then moved forward aggressively with Met inhibitors," said Dr. Bart Lutterbach of Merck, who studies Met in lung and gastric cancers.
Mutations and amplifications of Met may be relatively rare in many cancers, noted Dr. Lutterbach. But for patients whose tumors depend on Met signaling, blocking these signals will be necessary to treat the disease.
Over the last 20 years Met has been a tool for understanding how kinase receptors can be deregulated, said Dr. Morag Park of McGill University, who discovered the gene while working with Dr. Vande Woude at NCI.
"Met has led us to a much deeper understanding of signaling pathways involved in cancer," she added. "The important question to ask about Met now is whether it works in a synergistic way with other signals involved in cancer."
Dr. Park predicted that considerable "crosstalk" among signaling pathways will be found in cancer cells when the studies are possible.
A striking example of this phenomenon may have been discovered recently in lung cancer. When the signaling protein EGFR was blocked by a drug, lung cancer cells simply amplified Met to take its place and rendered the drug useless, researchers reported in the April 26 Science.
In light of this cooperation, a comprehensive understanding of how signals are transmitted in cells may be required to treat some cancers. And patients may one day take multiple drugs, as HIV patients do, in an effort to prevent resistance.
"By using combinations of targeted therapies, it should be possible to reduce the likelihood that tumors can escape the control of individual drugs," said Dr. Vande Woude.
At the same time, Met inhibitors may work synergistically with other inhibitors. Dr. Ravi Salgia of the University of Chicago and his colleagues have tested a Met inhibitor that cooperated with the drug rapamycin in some tumors.
Dr. Salgia is now focusing on how to identify lung cancer patients who may benefit from anti-Met therapy. These patients would have increased Met activity as a result of mutations, amplifications, or perhaps drug resistance.
"There are a lot of unanswered questions we need to figure out," said Dr. Salgia. "But working to understand pathways such as Met may open windows of opportunity for other therapies."
Phase II trials are underway for XL880, and positive results have been reported. Many other experimental agents are waiting in the wings.
"We need to move forward with these agents because they are the next generation of cancer therapies," said Dr. Patricia LoRusso of the Barbara Ann Karmanos Cancer Institute in Detroit, who presented results on XL880 at ASCO."We are finally starting to turn science into medicine, and it's exciting," she added.
- Edward R. Winstead