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The application of any particular biomarker in a given program is dependent on the nature of the disease under investigation. Biomarkers can be used to determine whether or not a candidate compound is capable of reaching the target of interest, provide an early indication of efficacy (or lack thereof), predict toxicity, and even identify patient populations that are more likely to respond to therapeutic agents. At the end of the day, the purpose of biomarkers and translational medicine is to increase the speed and efficiency of the identification of novel therapeutics.
Identifying biomarkers that facilitate the characterization of candidate compounds can have a significant impact on the various stages of drug discovery and development. Biomarkers that are indicative of efficacy can shorten clinical trials and decrease the number of patients exposed to new compounds. Safety risks can also be mitigated by identifying biomarkers that are indicative of potential risks. Termination of clinical programs due to poor performance in biomarker studies, whether by efficacy issues or the identification of safety risks, allows resources to be quickly redirected to more fruitful areas, thereby adding efficiency to the drug discovery and development process. Bringing these tools together through the concepts of translation medicine in a bench-to-bedside approach can also improve the use of resources at the earliest stages of drug discovery. Biomarkers of efficacy in disease states can be used to determine the validity of hypothetical therapeutic targets. Rapid validation or invalidation of a potential therapeutic target provides an opportunity to redirect resources to areas more likely to bear fruit.
Fig 1. Examples of biomarkers at different pharmacodynamic levels in the management of diseases. (Aronson, 2017)
2-deoxy-2-(18F) fluoro-d-glucose (FDG) was one of the first radioligands developed for PET imaging. FDG is a substrate for the glucose transporter, so it is rapidly absorbed by cells, and it is also a substrate for hexokinase, the enzyme responsible for the first step in glucose metabolism. Hexokinase phosphorylates FDG, producing FDG-6-phosphate, blocking further metabolism via the glycolysis pathway. As a result, FDG6-phosphate accumulated in the cells.
All cells use glucose. If all other conditions were equal, the distribution of FDG-6-phosphate would be uniform across the body. There are, however, important differences between normal cells and malignant cells. In many cases, the significantly greater energy demand of malignant cells is supported by the upregulation of both glucose transporters and hexokinase. This increases the uptake of FDG by certain types of malignancies relative to normal cells. The low levels of FDG-6-phosphate produced in normal tissues serve as a background for the higher levels of FDG-6-phosphate produced in cancerous tissues. These differences can be visualized using PET imaging techniques, providing a method of diagnosing and staging several different malignancies. This technique has been successfully applied to colorectal cancer, melanoma, lymphoma, and non-small-cell lung cancer.
It should also be clear that PET imaging agents such as FDG and other compounds that are selectively absorbed by malignant cells can be a very effective tool in the identification of new therapeutic agents. Tumor size and disease progression could be tracked over time in an appropriate animal model using a PET ligand. At the same time, animals can be treated with a candidate compound while monitoring for changes in tumor size and disease progression using the same PET ligand. PET imaging methods can be applied at the in vivo animal model stage or human clinical trials. In both cases, PET imaging techniques may provide insight into the utility of candidate compounds well ahead of the traditional survival endpoints.
Fig 2. FDG PET/CT in a patient marginal zone lymphoma. (Finessi, 2020)
Creative Biolabs provides a comprehensive suite of customized Drug Discovery services in a timely and cost-effective manner to satisfy your specific needs. Whether you have any questions about our services or about biomarkers, please contact us and we will provide you with a detailed explanation.
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