Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Abstract

PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non-tumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a phase I dose-escalation clinical trial of pictilisib. Time-and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition.

Cerebrospinal fluid ctDNA and metabolites are informative biomarkers for the evaluation of CNS germ cell tumors

“…A study showed that plasma levels of acetylcarnitine negatively correlated with tumor grade in patients with hepatocellular carcinoma 24 . Studies on plasma metabolites indicate that changes in the MAPK or PI3K pathways are associated with alterations in metabolites including amino acids, acylcarnitines, and phosphatidylcholines 25,26 . Therefore, we assumed that GCTs, often associated with mutations in either MAPK or PI3K pathways, exhibited decreased levels of acetylcarnitine and butyrlcarnitine.…”

Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation

“… 19 Metabolomic studies of the same inhibitor show that plasma metabolites can be useful dose-dependent biomarkers of the response to therapy. 20 …”

Metabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation

“…It provides insight into normal physiology and pathomechanisms, and tools to characterise phenotypes. In the context of drug discovery and development, metabolites provide accessible biomarkers (Ang et al 2017(Ang et al , 2016Griffiths et al 2010).This is particularly important where the availability of human tumour biopsies is limited and the use of surrogate tissues, e.g. plasma, is essential to assess target engagement.…”

“…50 Page 2 of 11 mediated effects, assessment of the compound non-tumour related effects has the potential to (i) identify biomarkers, (ii) gain better understanding of the mechanism of action and (iii) predict potential side effects earlier in the drug development process before the clinical phases. We have previously demonstrated that metabolomic signatures established in preclinical studies can be used clinically as biomarkers of target engagement and/or predictors of tumour and compound specific responses (Ang et al 2017(Ang et al , 2016. In these studies, a workflow to generate tumour specific and target related metabolomic signatures was successfully applied.…”

“…Initially, metabolomic changes in plasma induced by different pathway inhibitors in preclinical studies from tumour and in non-tumour bearing mice were measured. These preclinical data sets were used to generate target and tumour specific metabolomic signatures which were assessed later with plasma samples from patients in a Phase I clinical trial (Ang et al 2017(Ang et al , 2016Sarker et al 2015;Yang et al 2019).…”