When Gleevec burst onto the oncology drug scene several years ago, it did more than revolutionize the treatment of chronic myelogenous leukemia (CML), a rare but deadly cancer. Targeted therapiesand new buzzwords such as "rational design" and "smart drugs"became all the rage.
Targeted therapies are supposed to be neater and cleaner than the "shotgun" approach of chemotherapy. Such agents attempt to disrupt pathways unique to cancer cells, which they use to grow and communicate, and they theoretically leave normal cells alone and avoid the toxic side effects common with chemotherapy and radiation.
But finding the next Gleevec has turned out to be harder than many scientists thought, and disappointing results early on in the life of some targeted therapies has raised questions about target validation and clinical trial design.
"You have to know the specific drug target and the specific population of patients the agent may help in order to intelligently design an appropriate trial," said Charles Sawyers, M.D., of the University of California at Los Angeles, who moderated a forum on barriers to clinical testing of targeted agents at a meeting on molecular targets sponsored by the American Association for Cancer Research held last year in Boston. "We have great [potential cancer] inhibitors but we dont know how to test them intelligently. There remains a disconnect between cancer patients in the clinic and the science behind testing [potential targeted] drugs."
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"We think we should be smarter [in testing] because we understand what some of the targets are now, along with some of the molecular biology," said Louise Grochow, M.D., chief of the Investigational Drug Branch at the National Cancer Institute. "The reality is, we dont have much more understanding of this than we do regarding the cohort of patients traditional chemotherapy should work in and when a combination of different drugs should be tried."
Understanding Targets
"One of the challenges we have involves the extraordinary advances in technology that have allowed identification of many potential cancer cell targets and the ability to rapidly develop therapeutic agents that inhibit those targets," said Susan Arbuck, M.D., vice president and global head of the oncology therapeutic area at Aventis in Bridgewater, N.J., and a speaker at the AACR seminar.
"Drugs come to the clinic without the benefit of years of academic research that previously provided critical understanding of a target. We often know little about the targets role in tumor pathogenesis and growth, and how it interacts with other networks involved in these processes. In many cases, we dont know how to identify those tumors that are more likely to respond to the treatment."
Brian Druker, M.D., one of the key scientists who developed Gleevec, contends that targeted therapy development may face obstacles because "all too often we are treating patients too late, and we may be treating many of the less important, secondary genetic defects in the cancer." Advanced cancers have so many defects, said Druker, a Howard Hughes Medical Institute investigator at Oregon Health and Science University in Portland, that a targeted therapy may not be treating the right abnormality or the right set of patients. Gleevec "tells you the importance of targeting the early causal genetic defects in cancer," he said.
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What Went Wrong?
Iressa is expected to cause tumor shrinkage in 10% to 20% of patients with advanced lung cancer. Janet E. Dancey, M.D., senior investigator in the Investigational Drug Branch at NCI, called Iressa "one of the most promising drugs and therapeutic approaches aimed at many tumor types known to highly express EGFR." AstraZeneca moved quickly and efficiently in clinical development after seeing responses in large phase I trials, said Dancey.
"There were a lot of competitors in the field, and given that they had an agent that appeared to induce an anti-tumor response, they moved forward," she said, adding that Herceptin had only a 10% response in the initial phase II study in breast cancer patients. (Herceptin is a monoclonal antibody that was the first targeted therapy to earn approval by the FDA.)
Arbuck noted that, if scientists "had tried to develop Herceptin without knowing it was effective in tumors that are Her2-neu positive, they could have missed the activity. Thirty percent of breast cancer patients have that abnormality, and without selecting for those patients, we would have had a population in which the majority wouldnt have had a response and a low level of activity," she said. "That could be the issue in Iressa. We know that 10% to 20% of patients will respond, but we dont know how to identify them."
In some situations, said Druker, a company might invest in testing a potential targeted agent and conclude that the target is not very important to the cancer. In reality, the company may lack the necessary science to analyze patients and determine whether the target is activated or shut down.
"Many targeted agents will have to be tried empirically, because we dont have guiding examples of where a class of agents should work," said Druker.
Better preclinical models would help. According to Richard Pazdur, M.D., director of oncology drug products at the FDAs Center for Drug Evaluation and Research, the glaring lack of "good preclinical models to adequately address for what specific cancer a drug should be developedand if it should be developedmakes oncology drug development a particularly risky business. ... Companies dont want to enter into large expensive trials and have a negative finding," he said.
"Because science doesnt have good models to predict where the drug should be developed, were frequently left with sporadic findings from phase I studies for clues."
Grochow agreed. "We have very few engineered models where we can say, in this particular mouse model, these three things are what are causing this tumor," she said. "If we correct these three things, we can stop the cancer from growing."
What Can Be Done?
Many challenges remain in targeted therapy development. "How can companies predict for failure with preclinical studies?" Dancey asked. "And how can the molecular heterogeneity and subtypes of tumors be addressed, and how will the assays and tools be developed?"
"The question is, can we develop more intelligent ways of testing drugs?" Sawyers said. "The science of how to apply targeted drugs to patients in the clinic when the science of how to evaluate patients for targets isnt there yet. Thats the rate-limiting step in cancer drug development right now."
Both Arbuck and Sawyers see molecular profiling as part of the answer to choosing the best patients to receive a targeted agent and to incorporating results into trial design. "Taking a persons tumor and characterizing it molecularly and determining which drug or combination is effective for that particular patient would be an improvement over what is currently available," Arbuck said. "People have a better understanding today, with genomics and proteomics, of whats different in a cancer cell," which enables them to be smarter in choosing targets that are important to tumors.
The case is the same for identifying patient groups that could potentially benefit. "Once we do that, we can have smaller trials because well have a more homogeneous population," Arbuck said. "We should be able to demonstrate the benefit with a smaller number of patients, which should decrease the cost of development. If we could identify who benefits, then we would know who doesnt benefit; this might help by telling us where we need to direct efforts to identify the next generation of agents."
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