Monitoring pharmacodynamic and molecular drug targets in liquid biopsy: Exploratory study in liver cancer with modelling of EGFR Receptor engagement.

AIM: Liquid biopsy is minimally invasive (compared with tissue biopsy) and has previously been used to generate systems data regarding drug elimination via hepatic enzymes and transporters. This study extends quantitative assessment of systems parameters in liquid biopsy to pharmacodynamic (PD) and disease markers relevant to cancer development and therapeutics.

METHODS

Plasma extracellular vesicles (EVs) were extracted from 29 liver cancer donors. Cell-free RNA from EVs was subjected to RNAseq, allowing differential expression of PD/disease markers to be investigated relative to healthy baseline. Proteomics of matched liver membrane fractions was used to assess correlation of hepatic abundance with expression in plasma EVs. As a case example, quantitative systems pharmacology (QSP) modelling was used to evaluate EGFR occupancy with its ligand EGF and the EGFR-specific mAb, cetuximab.

RESULTS

Expression of 406 PD markers and drug targets was monitored in plasma-derived EVs (including >130 molecular drug targets and >240 disease markers). Differential expression analysis revealed 18 dysregulated pathways involved in cell growth, proliferation, invasion, apoptosis, angiogenesis and immune regulation. EV expression of 33 markers with corresponding liver abundance lacked correlation, reflecting ubiquitous/extrahepatic expression of PD markers. QSP modelling of EGFR receptor occupancy with standard-dose cetuximab in the presence of EGF demonstrated suboptimal receptor blockade by the mAb (~80%) in patients with high EGFR expression.

CONCLUSION

This study demonstrated the utility of liquid biopsy in monitoring PD targets and informing QSP models of disease. The approach may be used to guide drug dosing adjustment based on disease progression or remission.