Novel Transcriptomic Biomarkers

Disease- and toxicity-specific transcriptional and metabonomic biomarkers are an as yet largely untapped reservoir; however, publications investigating such biomarkers have become increasingly visible in the literature (Fielden and Kolaja, 2006; Foster et al., 2006; Robertson et al., 2007). In a retrospective review of several years of toxicogenomic analyses of drug safety studies, bio-markers of pharmacology were readily identified in 21% of studies (40% of drug targets) (Foster et al., 2006). An unvalidated version of such an mRNA signature is that of proliferation inhibition observed consistently in the liver of rats given oncologics. A set of such genes is illustrated in Table 3.

These observations can readily be adapted to transcriptomic signatures and used to determine which doses, for example in a toxicology study, demonstrate compound efficacy. When combined with traditional endpoint data, a therapeutic index may then be derived. This approach is particularly useful when the pharmacology of a compound has not been evaluated in the test species. Although early transcriptomic signatures consistent with previously identified pathology are frequently observed (in approximately 50% of studies of target tissues profiled at times preceding pathology), the target tissues involved are rarely analyzed transcriptionally such that finding valid predictive signatures will continue to be problematic (Fielden and Kolaja, 2006).

Transcriptomic signatures may also provide insight toward pharmacologic effect in distinct patient groups. The demonstration of increased expression of wild-type and mutant Kras by both immunohistochemistry and transcrip-tional profiling or real-time polymerase chain reaction (RT-PCR) led to the hypothesis that the selection of certain patients dosed with EGFR inhibitors based on the expression and presence of mutation could markedly increase the responder rate of patients (Lièvre et al., 2006; Di Nicolantonio et al., 2008). The ability to triage patient groups and eliminate patients for whom potentially toxic medicines offer no benefit is clearly a huge advance in the practice of oncology.

TABLE 3 Genes Commonly Changed by Diverse Oncologic Agents in Rat Liver

Gene

Transcriptional Change

Gene Function

Gene Name

Rrm2

Repression

Proliferation

Ribonucleotide

Project Management Made Easy

Project Management Made Easy

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