Biomarkers
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Figure 1
PubMed citations referencing biomarker as a key word between 2000-2009
order to drive the utility of biomarkers as efficient- ly as possible into research and clinical applica- tions. A significant example of this is the Biomarkers Consortium, which was formally estab- lished in 2006 and brings together the resources of the NIH, medical and academic communities with the private sector represented by pharmaceutical, biotechnology, diagnostic and instrumentation companies. Such open-source precompetitive col- laborations, funded by national or international programmes such as EU-FP6 in Europe or PhRMA in the USA, offer both challenges and significant opportunities, as reviewed recently following com- pletion of the first Biomarkers Consortium project demonstrating potential utility of adiponectin as predictor of metabolic responses to PPAR agonists in diabetic patients3,4. Not surprisingly, important lessons learned from this inaugural study include the need for establishing common standards and definitions of successful biomarker qualification in an open data-sharing environment.
Application areas for biomarkers Biomarker identification and validation has been applied to a wide variety of therapeutic areas including neurological disease, metabolic disor- ders, and immune dysregulation, but perhaps the most predominant field of application lies in oncol- ogy. As reviewed by Marrer and Dieterle5, prog- nostic biomarkers are presently available to guide oncologists in formulating optimal treatment plans for their patients, with the two most cited exam-
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ples being commercial kits for stratification of breast tumours based on the trancriptional profile of 70 genes (MammaPrint® Assay, Agendia BV) or 21 genes (Oncotype DX® Assay, Genomic Health Inc), respectively. These assays allow for clinical categorisation of patients for risk of disease recur- rence, and therefore helps establish the need for follow-on treatment. The application of targeted cancer therapies fall under the rubric of predictive biomarkers, which address the potential response or insensitivity of the tumour to a particular thera- py. In this case, companion diagnostic tests must be co-developed with the drug through clinical trials in order to not only demonstrate drug efficacy but also validity of the predictive test. One of the best known examples of a predictive marker is the Her2/neu diagnostic test for treatment of Her2 positive metastatic breast cancer with Herceptin. A wide variety of accumulated studies have been published in the evaluation of potential diagnostic biomarkers for cancer, with varying degrees of suc- cess. Recently, an integrated systems biology approach was advanced by Kulasingam et al6 in order to identify promising ovarian cancer mark- ers. This strategy included proteome and transcrip- tome comparisons of tissue, serum, proximal flu- ids, cancer cell lines and animal models from a variety of sources. This group short-listed 33 can- didate proteins common to three datasets, and two proteins which were overexpressed in four of the datasets studied. Both of these proteins were known to be associated with invasive ovarian can- cer, and thus served to support the integrated approach to biomarker identification. The application of biomarkers to improved phar- macodynamic and safety testing for the pre-clini- cal/clinical phase of drug development is also an important application area. This has already been well established through the clinical use of the microarray-based AmpliChip® CYP450 test (Roche Diagnostics Corp) which analyses patient genotypes for variant alleles of cytochrome P450 (CYP) genes, CYP2D6 and CYP2C19, which corre- late with different phenotypic effects on drug metabolism. Recently, the first comprehensive set of studies supporting seven renal biomarkers for measuring drug toxicity were published by the Predictive Safety Testing Consortium (PSTC), rep- resenting a collaboration of scientists from 17 pharmaceutical/biotechnology companies, five aca- demic institutions, and the FDA/EMEA7. One of the key principles applied to this effort was the adoption of well-defined criteria for analytical assay validation as outlined by the NIH Chemical Genomics Center and guidances contained in the
Drug Discovery World Summer 2010
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