Title: Biomarker-driven development of cancer chemopreventive agents: a new paradigm
Funder: Cancer Research UK

Abstract: Background_x000D_ Although chemoprevention offers enormous potential to reduce cancer burden in society, preclinical development of new agents, the choice of dose and subsequent clinical assessment pose major difficulties not addressed by current strategies. A new development paradigm is essential to enable the discipline of chemoprevention to progress._x000D_ _x000D_ Aims/objectives_x000D_ We aim to define a new development strategy for chemoprevention agents using aspirin, curcumin and resveratrol as model compounds. The programme has three objectives, the first being to improve current preclinical testing regimes to better reflect the clinical scenario in which chemopreventive agents will be used. This will optimise identification of compounds most likely to prevent human cancers. The second is to identify novel pharmacodynamic biomarkers modulated by efficacious doses of these agents. Finally, we will evaluate the most promising surrogate efficacy biomarkers in a pilot clinical study involving patients at high risk of colon cancer, with biomarker changes and adenoma recurrence as the endpoints._x000D_ _x000D_ Methods _x000D_ Towards the first aim we will employ more clinically relevant models for assessing chemopreventive activity, namely long-term culture of adenoma and syngeneic colorectal carcinoma cells with concentrations of agents attainable in humans. In parallel, we will explore stem-like cells as a target for chemoprevention using primary human premalignant and cancer cells. The Lgr5Cre+Apcfl/fl mouse model of colorectal carcinogenesis will be used to discover plasma proteins modulated by intervention using LC-MS/MS based proteomics; immunohistochemistry and FACS analysis of intestinal tissue will reveal phenotypic alterations including changes to the stem cell compartment, and degree of apoptosis/proliferation. We will also identify proteins that bind directly to the three compounds using novel protein pull-down assays to elucidate pathways affected and rationalise the protein expression data. Clinical evaluation involves assessing variation of potential biomarker(s) in healthy volunteers. Subsequently, an intervention study with aspirin and curcumin/resveratrol will address biomarker utility in patients at high-risk of colon cancer; plasma biomarker levels will be measured by LC-MS/MS-SRM over 12 months and correlated with exposure and adenoma recurrence. _x000D_ _x000D_ How this research will be used_x000D_ This work will establish and interrogate a new paradigm for the development of chemoprevention agents through use of clinically relevant test systems and incorporation of pharmacodynamic biomarkers at an early stage in the process. Additionally, mechanistic understanding of how aspirin, curcumin and resveratrol exert activity in vivo will be greatly enhanced. The combined results will be used to devise a model framework, which could transform the future development of chemopreventive agents.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS