Predicting toxicity in the drug development pipeline

University College Dublin researchers have reported in Molecular & Cellular Proteomics on a proof-of-principle study that may benefit the pharmaceutical industry in the future by providing a roadmap for large scale pre-clinical toxicology biomarker verification studies.

It is not currently possible to predict accurately and at an early stage whether there are toxicity issues with candidate drugs. This shortcoming of existing toxicology evaluation methods can not only create a bottleneck in the pipeline but can sometimes lead to the withdrawal of drugs from the market.

The study involved the molecular profiling of models that had been exposed to known toxic insults in an effort to derive the associated biomarker signatures. Forty-eight candidate biomarkers of liver toxicity were assembled from a discovery proteomics screen of liver in a hepatotoxicant treated rat model using label free liquid chromatography mass spectrometry (LC-MS); a previous transcriptomics study of the sample samples and from literature sources.

The team developed and optimised a selected reaction monitoring assay (SRM) in order to quantify the proteins in this putative biomarker panel. This revealed a panel highly enriched for proteins that had been changed significantly as a result of toxicant exposure .   

Dr. Ben Collins, first author and Agilent UCD Newman Fellow, explains, “The idea was to use transcriptomics,  and proteomics and to combine the data to provide earlier markers . Although this study focused on one hepatotoxic compound, there is sufficient flexibility in the approach used to allow medium to high throughput for large scale verification studies involving large numbers of well- defined toxicants and ultimately for more sensitive toxicology evaluation for drugs under early development”.

Team leader and corresponding author, Professor Steve Pennington adds, “We are now working to extend this approach to more readily accessible sample types, such as blood, and are applyijng it in other studies for diagnostics for chronic conditions, such as cancer, cardiovascular disease, and arthritis. With supporti from Agilent are now establishing a dedicated lab to undertake these SRM-based validation studies”.

More information: Collins, BC et al; Development of a pharmaceutical hepatotoxicity biomarker panel using a discovery to targeted proteomics approach. Molecular & Cellular Proteomics (2012) doi: 10.1074/mcp.M111.016493

add to favorites email to friend print save as pdf

Related Stories

Cancer biomarkers re-evaluated

Jul 19, 2012

(Medical Xpress) -- Researchers from ETH Zurich have developed a procedure to test the clinical benefits of cancer biomarkers. The method could radically shorten the path from the lab to their application.

Recommended for you

Mystery of the reverse-wired eyeball solved

Feb 27, 2015

From a practical standpoint, the wiring of the human eye - a product of our evolutionary baggage - doesn't make a lot of sense. In vertebrates, photoreceptors are located behind the neurons in the back of the eye - resulting ...

Neurons controlling appetite made from skin cells

Feb 27, 2015

Researchers have for the first time successfully converted adult human skin cells into neurons of the type that regulate appetite, providing a patient-specific model for studying the neurophysiology of weight ...

Quality control for adult stem cell treatment

Feb 27, 2015

A team of European researchers has devised a strategy to ensure that adult epidermal stem cells are safe before they are used as treatments for patients. The approach involves a clonal strategy where stem cells are collected ...

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.