NEWS

Biomarkers, Animal Models Key in Progress of Chemoprevention

Mike Miller

Tamoxifen and celecoxib, used, respectively, for prevention of some types of breast and colon cancers, are the only drugs approved by the U.S. Food and Drug Administration to help reduce the risk of cancer.

Although chemoprevention holds great promise, challenges ahead include identifying refined clinical markers, discovering better predictive mouse models, and developing genomic and proteomic analyses that can identify precursor lesions.

Biomarkers are one key to developing new prevention drugs and getting them to market in a more timely manner, said David S. Alberts, M.D., Arizona Cancer Center, Tuscon. He suggested that phase II clinical trials offer the ideal model for testing surrogate end point biomarkers.



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Dr. David S. Alberts

 
Alberts noted of tamoxifen and celecoxib that, "neither drug was developed with studies that used surrogate end point biomarkers, which are needed for us to effectively develop new agents." Unlike tamoxifen or celecoxib, drugs developed using surrogate end point biomarkers might have a more precise target, leading to lower toxicity and a greater clinical benefit.

Different Mechanisms of Action

Alberts said, however, that for any given agent there may be many different mechanisms of action, so a drug targeting prevention of a mutation in the p53 gene could potentially cause benefit or harm to other genes.

Additionally, there are two main obstacles to using biomarkers as end points in clinical trials, said Alberts. The expression of a biomarker can vary throughout a single tumor, and expression can change over time in the natural history of the cancer.

Approaches to chemoprevention other than through biomarkers were discussed at this year’s annual meeting of the American Association for Cancer Research in New Orleans. William Nelson, M.D., Ph.D., assistant professor of oncology, Johns Hopkins University School of Medicine, Baltimore, said that "most clues about chemopreventive agents have come from epidemiological studies, with many such studies showing that environmental effects can vary risk." Environmental impact can often be neglected in many study designs, he added.

Li Mao, M.D., associate professor of medicine at the University of Texas M. D. Anderson Cancer Center, Houston, echoed his opinion. Li noted that "we must have both a cessation program (one type of environmental approach) and a chemopreventive agent but can’t do them separately."

Mao pointed to the Finnish studies on current smokers and vitamin E as an example. He noted that these studies showed that an intervention could cause harm. He added that a new agent must show a biological effect before it is put into clinical study.

In his own work in looking at vitamin A analogues to reduce the activity of telomerase in lung cancer, he said he must be wary of the fact that vitamin A is a complex chemical with many analogues, one of which affects apoptosis, or the longevity of the cell. Factors like this must be taken into consideration when creating any chemopreventive agent, he said.

Animal Models

Developing animal models for chemoprevention presents its own challenge. Jeffrey E. Green, M.D., of the National Cancer Institute’s Laboratory of Cell Regulation and Carcinogenesis, cautioned that "some findings in colon cancer mice, which were very good models, actually led to clinical trials in humans which resulted in an increase in cancer."

Green suggested that good models should have defined natural histories, stages of tumor progression, and hormone receptor status. "Most work to date has been in rat models that had chemically induced cancers," he said. "Mice are transgenic and hormone independent, which should lead to more reliable models." The Mouse Models of Human Cancers Consortium established by the NCI in December 1999 is one of the leading sources for development of mouse models for chemoprevention and treatment research.

Estrogen Receptors

One of the more active areas of chemoprevention research development is the search for an agent that acts on estrogen receptor-negative breast cancers, because tamoxifen has not been shown to be effective for these types of cancers. Following up on Green’s work, Karen Johnson, M.D., Ph.D., Division of Cancer Prevention, NCI, is looking into preclinical studies and clinical trials that would use gene cluster pattern identification derived from mouse models to assemble molecular profiles of estrogen receptor-negative versus estrogen receptor-positive cancers.



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Dr. Karen Johnson

 
In proposed exploratory clinical studies, researchers would sample tissue for biomarkers before and after exposure to a potential chemopreventive agent to see if any of them might prove effective. "We think that estrogen receptor-negative breast cancer is probably more than one disease, which is perhaps why we’ve found very little clinical benefit for most agents that have been tested so far," said Johnson. Initial trials may involve a cohort of high-risk patients, such as women with BRCA mutations or those with abnormal tissue.

In considering what it might take to develop an armamentarium of effective chemopreventive agents, Nelson questions whether any one agent alone could show an effect. Additionally, he urges that "efforts, other than drug development, must be undertaken to help reduce risk."



             
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