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New concepts and challenges in the clinical translation of cancer preventive therapies: the role of pharmacodynamic biomarkers.

Brown K, Rufini A - Ecancermedicalscience (2015)

Bottom Line: Implementation of therapeutic cancer prevention strategies has enormous potential for reducing cancer incidence and related mortality.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.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.

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.

No MeSH data available.


Related in: MedlinePlus

Proposed pathway for the preclinical development and early clinical evaluation of potential cancer prevention therapies.
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figure1: Proposed pathway for the preclinical development and early clinical evaluation of potential cancer prevention therapies.

Mentions: This article focusses on the general development pathway for preventive agents (Figure 1) and highlights key areas relating to the discovery of PD or predictive biomarkers that warrant greater consideration in order to maximise the chances of success in future randomised controlled clinical trials.


New concepts and challenges in the clinical translation of cancer preventive therapies: the role of pharmacodynamic biomarkers.

Brown K, Rufini A - Ecancermedicalscience (2015)

Proposed pathway for the preclinical development and early clinical evaluation of potential cancer prevention therapies.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664507&req=5

figure1: Proposed pathway for the preclinical development and early clinical evaluation of potential cancer prevention therapies.
Mentions: This article focusses on the general development pathway for preventive agents (Figure 1) and highlights key areas relating to the discovery of PD or predictive biomarkers that warrant greater consideration in order to maximise the chances of success in future randomised controlled clinical trials.

Bottom Line: Implementation of therapeutic cancer prevention strategies has enormous potential for reducing cancer incidence and related mortality.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.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.

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.

No MeSH data available.


Related in: MedlinePlus