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Intermediate biomarkers of precancer and their application in chemoprevention
G J Kelloff1, W F Malone, C W Boone
1Chemoprevention Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Abstract:
The Chemoprevention Branch of the National Cancer Institute has established a program for the development of safe and effective cancer chemopreventive agents. This program includes identification of new agents, testing for efficacy in vitro and in animals, studies in animals to model clinical use, and preclinical toxicity and metabolism evaluation. Ultimately, the most promising agents progress to clinical trials. The long period required for cancer onset presents a significant challenge to the design of clinical trials for chemoprevention. Phase III trials in which cancer reduction is the endpoint require large subject groups (tens of thousands) and follow-up duration of more than five years. Because of these requirements, the cost of such trials are high. The Chemoprevention Branch is addressing this challenge by expansion of the preclinical and Phase II clinical efficacy efforts to include intermediate biomarkers of carcinogenesis as study endpoints. The Chemoprevention Branch's studies focus on the development of biomarkers with high reliability and predictive value for cancer. Both single markers and batteries of complementary and parallel markers are evaluated. Among the criteria for biomarkers for chemoprevention studies are the following: (1) differential expression in normal and high risk tissue, (2) appearance early in carcinogenesis (the earlier a reliable biomarker appears, the greater is the chance for successful intervention with a chemopreventive agent), (3) high sensitivity, specificity, and accuracy relative to cancer, (4) ease of measurement (use of non-invasive techniques and small tissue samples is preferable), (5) demonstration of modulation by chemopreventive agents, and (6) correlation of modulation with decreased cancer incidence.
Insights
The National Cancer Institute
Area of Science:
- Oncology
- Cancer Prevention Research
- Biomarker Development
Background:
- The National Cancer Institute's Chemoprevention Branch develops cancer chemopreventive agents.
- Traditional Phase III chemoprevention trials are lengthy, costly, and require large patient cohorts.
- Cancer onset's long latency poses a significant challenge for clinical trial design.
Purpose of the Study:
- To address challenges in cancer chemoprevention clinical trials.
- To develop reliable intermediate biomarkers for carcinogenesis.
- To improve the efficiency and reduce the cost of chemoprevention studies.
Main Methods:
- Evaluating new chemopreventive agents through in vitro, animal, and preclinical studies.
- Developing and validating intermediate biomarkers of carcinogenesis as study endpoints.
- Assessing biomarkers for reliability, predictive value, and ease of measurement.
Main Results:
- Biomarkers offer a promising strategy to overcome clinical trial design challenges.
- The Chemoprevention Branch focuses on biomarkers with high reliability and predictive value.
- Criteria for biomarker selection include early appearance in carcinogenesis and modulation by agents.
Conclusions:
- Utilizing intermediate biomarkers can significantly enhance cancer chemoprevention research.
- Biomarker-driven trials allow for more efficient and cost-effective evaluation of chemopreventive agents.
- This approach supports the development of safer and more effective cancer prevention strategies.