Molecular pharmacology and biomarkers

Upon determination of the optimal conditions of use of a novel compound, the next challenge is to facilitate and strengthen its progress through the drug development process towards the clinic. This translational research is based on the discovery of molecular biomarkers of the efficacy of treatment.

Our first class of biomarkers help in determining the mechanism of action of new drugs and highlight potential avenues for the therapy, however, these markers are not directly translatable to the clinic.

• The detection of modifications to the vasculature post-treatment can be studied by functional histology. The diffusion of fluorescent dyes of various molecular weights enable the analysis of microvessel density (CD31 staining), as well as vessel functionality and permeability (dextran-FITC & Hoescht).
• The quantification of hypoxia could be performed by immunohistochemistry (HIF1a).

Our second class of biomarkers can be directly translated to the clinic and can be used to monitor patient response to treatment.

• Target expression in treated versus untreated tumors could be studied by western blot, quantitative RT-PCR or proteomic analysis.
• Circulating biomarkers could be analyzed to assess the tumor response to a specific treatment (e.g. CA19.9, PSA, CEA).
• Immune response characterization could be performed by analyzing cytokine production, expansion and activation of immune cell populations and the infiltration of immune cells into the tumors. The use of syngeneic models (immunocompetent animals) or huPBMC reconstituted mouse models are often better adapted immune-based in vivo studies.
• Innovative biomarker determination by analysing the protein profile of animal serum before and after treatment using a proteomic analysis platform (2D electrophoresis coupled to HPLC/MS-MS).

This step enables us to better define the molecular changes in response to the pharmacological activity of a new drug. We can then better define the use of the new compound and facilitate its passage to the clinic.