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Title: New concepts and challenges in the clinical translation of cancer preventive therapies: the role of pharmacodynamic biomarkers.
Authors: Brown, Karen
Rufini, Alessandro
First Published: 24-Nov-2015
Presented at: WP2 EurocanPlatform meeting: European recommendations for biomarker-based chemoprevention trials, October 13–14, 2014, at the European Institute of Oncology, Milan, Italy.
Publisher: Cancer Intelligence Ltd.
Citation: ecancermedicalscience 2015, 9:601
Abstract: Implementation of therapeutic cancer prevention strategies has enormous potential for reducing cancer incidence and related mortality. Trials of drugs including tamoxifen and aspirin have led the way in demonstrating proof-of-principle that prevention of breast and colorectal cancer is feasible. Many other compounds ranging from drugs in widespread use for various indications, including metformin, bisphosphonates, and vitamin D, to dietary agents such as the phytochemicals resveratrol and curcumin, show preventive activity against several cancers in preclinical models. Notwithstanding the wealth of opportunities, major challenges have hindered the development process and only a handful of therapies are currently approved for cancer risk reduction. One of the major obstacles to successful clinical translation of promising preventive agents is a lack of pharmacodynamic biomarkers to provide an early read out of biological activity in humans and for optimising doses to take into large scale randomised clinical trials. A further confounding factor is a lack of consideration of clinical pharmacokinetics in the design of preclinical experiments, meaning results are frequently reported from studies that use irrelevant or unachievable concentrations. This article focuses on recent findings from investigations with dietary-derived agents to illustrate how a thorough understanding of the mechanisms of action, using models that mimic the clinical scenario, together with the development of compound-specific accompanying pharmacodynamic biomarkers could accelerate the developmental pipeline for preventive agents and maximise the chances of success in future clinical trials. Moreover, the concept of a bell-shaped dose-response curve for therapeutic cancer prevention is discussed, along with the need to rethink the traditional 'more is better' approach for dose selection.
DOI Link: 10.3332/ecancer.2015.601
eISSN: 1754-6605
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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