A serious bottleneck in the drug development pipeline is the inability of current pre-clinical toxicology evaluation methods to predict early on, and with good accuracy, that a drug candidate will have to be removed from development due to toxicology/safety issues. The InnoMed PredTox consortium attempted to address this issue by assessing the value of using molecular profiling techniques (proteomics, transcriptomics, and metabonomics), in combination with conventional toxicology measurements, on decision making earlier in pre-clinical safety evaluation. In this study, we report on the SELDI-TOF-MS proteomics component of the InnoMed PredTox project. In this large scale, multi-site, multi-compound study, tissue and plasma samples from 14-day in vivo rat experiments conducted for 16 hepato- and nephro-toxicants with known toxicology endpoints (including 14 proprietary compounds and 2 reference compounds) were analyzed by SELDI-TOF-MS. We have identified seven plasma proteins and four liver proteins which were shown to be modulated by treatment, and correlated with histopathological evaluations and can be considered potential biomarker candidates for the given toxicology endpoints. In addition, we report on the intra- and inter-site variations observed based on measurements from a reference sample, and steps that can be taken to minimize this variation.
- Animal proteomics
- Pre-clinical safety
- Systems toxicology
Collins, B. C., Sposny, A., McCarthy, D., Brandenburg, A., Woodbury, R., Pennington, S. R., Gautier, J-C., Hewitt, P., & Gallagher, W. M. (2010). Use of SELDI MS to discover and identify potential biomarkers of toxicity in InnoMed PredTox: A multi-site, multi-compound study. Proteomics, 10(8), 1592-1608. https://doi.org/10.1002/pmic.200900608