Imaging technology reveals the complexity of biomarkers

1st April 2013

Lack of efficacy is the main cause for failure of clinical trials. Often, especially in the case of strongly diverse diseases like cancer, this is due to the fact that only a subset of patients express the responding phenotype.

Therefore, appropriate biomarkers are urgently needed in the clinical drug development process for patient population profiling towards individualised medicine. The functional complexity of disease mechanisms calls for a combinatorial approach to designing screens that can accurately identify specific, yet comprehensive biomarkers.
Furthermore, patient-specific disease-course predictions would be highly valuable to prevent disease aggravation or progression. A promising approach to individualised medical treatment or disease management lies in the analysis of heterogeneous cellular systems in combination with bioinformatic analysis of multiparametric data.
Imaging has many advantages when it comes to analysing cells or tissues, especially as novel imaging technologies enable the integration of morphological data with molecular imaging.

Light microscopy is one of the basic tools towards our understanding of biology and in recent times, the advances in labelling and imaging technologies have improved our ability to monitor complex molecular processes.

Examples like the Her2 gene and Herceptin or the EGFR gene and Erbitux show that screening of patients for genes or genetic mutations to determine appropriateness of a specific treatment is already a reality. However, potent combinatorial biomarkers are needed to truly utilise the potential of many pharmaceuticals, as well as minimise these drugs’ limitations.

MelTec has developed an ultra high content analysis technology that has the capability to provide combinatorial, cell-based biomarkers. The technology is called MELK and it is a robotic whole-cell imaging technology that integrates cell biology and biomathematical tools to simultaneously visualise dozens of proteins in a structurally intact cell or tissue.

The visualised information is then processed through the company’s data analysis software, enabling the identification of protein networks that play a crucial role in biological processes.

By screening for changes in the distribution of all possible combinations of proteins upon drug treatment or existence of disease, MelTec can identify very specific combinatorial biomarkers for tox analysis, lead compound selection and clinical monitoring.

One drawback to classical proteomic technologies is that they require tissue homogenisation, thereby losing sensitivity and topological information. In this respect immunohistochemistry (IHC) offers a major advantage, because the specific location of the target within the tissue can be determined. This can be critical, since, for example, tumours also contain stroma, fibroblasts, immune cells, blood vessels, etc. The MELK technology platform is able to stain more than 100 proteins in the same tissue section, which transforms IHC into a proteomics technology and combines the combinatorial power of proteomics with the topological advantages of IHC. MELK can monitor multiple markers and pathways from very small blood or tissue samples in their natural biological context, which makes it the optimal method for the emerging application of ‘-omic’ technologies in patient stratification and monitoring.

Dr Ronald Koop is with MelTec GmbH & Co KG, Magdeburg, Germany.





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