UCLA researchers in the Department of Molecular and Medical Pharmacology have identified kinase inhibitors that block glucose consumption and for which [18F]FDG PET can be used as a biomarker, potentially aiding in the early assessment of therapeutic regimen and faster clinical trials.
BACKGROUND:
Pharmacodynamic biomarkers of drug efficacy are critically important in the clinical development of that drug. An ideal biomarker is non-invasive, provides information on the drug action at its specific site of action, can be evaluated rapidly after administration of the drug, and tracks with the desired long-term effect of that drug. Such a biomarker can be used to provide early data on whether a drug is having its desired effect, which in turn can (for example) be used to rapidly accelerate dosing studies or to distinguish responding patients from non-responding patients early in a clinical trial.
INNOVATION:
Work from the Clark Lab has identified 11 clinically relevant kinase inhibitors for which early inhibition of glucose consumption, measured non-invasively by [18F]FDG PET, can be used as a pharmacodynamic biomarker of kinase inhibitor efficacy. By utilizing luminescence-based high-throughput screening, the researchers found a series of 11 kinase inhibitor compounds that selectively inhibited glucose consumption in lung cancer cell lines. These kinase inhibitors had long-term anti-cancer effects both in cell culture and mouse models, suggesting that measuring the tumoral glucose consumption after drug treatment could be a predictive biomarker for drug efficacy. Importantly, glucose consumption in cancer patients is routinely measured with [18F]FDG positron emission tomography (PET). Therefore, this technology is readily accessible in the clinic as an early assessment of kinase inhibitor efficacy and can be readily integrated into clinical trial designs.
POTENTIAL APPLICATIONS:
• Clinical biomarker to rapidly predict cancer drug efficacy
• Personalized medicine
ADVANTAGES:
• A non-invasive method by PET scan
• Early assessment of drug efficacy, as soon as 24-hour post-treatment
• The underlying mechanism has been identified
• Discovery of new clinically relevant anti-cancer KIs
DEVELOPMENT-TO-DATE: The therapeutic target is identified. Hits are identified and verified in cell culture and mouse models using PET scan.
RELATED PAPERS: Ghezzi C et al. Nat Commun. 2019;10(1):5444.