Predicting toxicity in the drug development pipeline

July 19, 2012

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

Related Stories

New prostate cancer biomarkers move closer to clinical use

June 17, 2011

Conway Fellow, Professor William Watson and Professor John Fitzpatrick, UCD School of Medicine and Medical Science and Mater Misericordiae University Hospital recently received a translational research award for the validation ...

GEN reports on nanotechology's impact on mass spectrometry

August 4, 2011

A move toward smaller and smaller sample sizes is leading to a new generation of mass spectrometry instrumentation, reports Genetic Engineering & Biotechnology News (GEN). From a specific application point of view, novel ...

Cancer biomarkers re-evaluated

July 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

A cheaper, high-performance prosthetic knee

July 30, 2015

In the last two decades, prosthetic limb technology has grown by leaps and bounds. Today, the most advanced prostheses incorporate microprocessors that work with onboard gyroscopes, accelerometers, and hydraulics to enable ...

Crystal clear images uncover secrets of hormone receptors

July 31, 2015

Many hormones and neurotransmitters work by binding to receptors on a cell's exterior surface. This activates receptors causing them to twist, turn and spark chemical reactions inside cells. NIH scientists used atomic level ...

Flow means 'go' for proper lymph system development

July 27, 2015

The lymphatic system provides a slow flow of fluid from our organs and tissues into the bloodstream. It returns fluid and proteins that leak from blood vessels, provides passage for immune and inflammatory cells from the ...

0 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.