Abstract

Preclinical Identification to Clinical Validation of Plasma Metabolomic Signature of Novel Signal Transduction Inhibitors

Florence Raynaud, Group Leader, The Institute of Cancer Research

Modern anticancer drug development is increasingly reliant on the assessment of biomarkers. The limited tumour sampling possible in a clinical study has shifted the matrix studied towards surrogate tissues and circulating biomarkers. We assessed the utility of plasma metabolomics by LC-MS as potential pharmacodynamic biomarkers of novel signal transduction inhibitors. Consistent changes in plasma metabolite levels with modulation of the PI3K pathway were identified from preclinical models by comparing genetically engineered PTEN+/- mice with wild-type littermate controls; athymic mice with/without PTEN-/- human tumour xenografts and changes following treatment using a PI3K inhibitor. Target/pathway-specificity was evaluated by comparing these changes with those following treatment with carmustine, a chemotherapeutic agent, or a MEK inhibitor. The implicated plasma metabolites include amino acids, carnitine derivatives and lipids. In the clinical setting, the impact of time-of-day and food intake on the biomarker candidates was evaluated. Despite physiological variations, consistent changes in the biomarker candidates could be observed following treatment with either a PI3K or MEK inhibitor in plasma from human tumour xenograft-bearing mice and patients with advanced solid cancers. These data suggest that plasma metabolomics is a valid strategy for monitoring pharmacodynamic effects of novel anticancer agents.