A platelet biomarker for assessing phosphoinositide 3-kinase inhibition during cancer chemotherapy

Abstract

Thrombin cleavages of selective proteinase-activated receptors (PAR) as well as PAR-activating peptide ligands can initiate the phosphoinositide 3-kinase (PI3K) signaling cascade in platelets. Downstream to this event, fibrinogen receptors on platelets undergo conformational changes that enhance fibrinogen binding. In our study, we used this phenomenon as a surrogate biomarker for assessing effects on PI3K activity. Our method, using flow cytometric measurement of fluorescent ligand and antibody binding, uncovered a 16-to 45-fold signal window after PAR-induced platelet activation. Pretreatment (in vitro) with the PI3K inhibitors wortmannin and LY294002 resulted in concentration-dependent inhibition at predicted potencies. In addition, platelets taken from mice treated with wortmannin were blocked from PAR-induced ex vivo activation concomitantly with a decrease in phosphorylation of AKT from excised tumor xenografts. This surrogate biomarker assay was successfully tested (in vitro) on blood specimens received from volunteer cancer patients. Our results indicate that measurement of platelet activation could serve as an effective drug activity biomarker during clinical evaluation of putative PI3K inhibitors. [Mol Cancer Ther 2007;6(9):2600 -7]

Dextran sulphate induces fibrinogen receptor activation through a novel Syk-independent PI-3 kinase-mediated tyrosine kinase pathway in platelets

“…PI3K has been shown to play an essential role in platelet aggregation (42) and αIIbβ3 activation (43). Our current results demonstrate that PI3K activity is required for DxS-mediated platelet aggregation and PI3Kβ is the primary isoform involved in this pathway.…”

First‐in‐human trial of the PI3Kβ‐selective inhibitor SAR260301 in patients with advanced solid tumors

“…11 The predicted SAR260301 concentrations required to completely inhibit the PI3K pathway were derived from an ex vivo platelet pAktinhibition assay. 11 The predicted SAR260301 concentrations required to completely inhibit the PI3K pathway were derived from an ex vivo platelet pAktinhibition assay.…”

“…SAR260301 activity was assessed using a plateletinhibition assay, which can serve as a surrogate biomarker assay in patients with cancer. 11 The predicted SAR260301 concentrations required to completely inhibit the PI3K pathway were derived from an ex vivo platelet pAktinhibition assay. Biologically active concentrations (based on preclinical modeling) were reached at the highest doses tested; however, SAR260301 was rapidly cleared, and exposure associated with antitumor activity in preclinical studies was not maintained.…”

“…9 The PI3Kb isoform is involved in regulating platelet function. 11 This phase 1, first-in-human study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of the selective PI3Kb inhibitor SAR260301 (clinicaltrials. 11 This phase 1, first-in-human study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of the selective PI3Kb inhibitor SAR260301 (clinicaltrials.…”

“…10 Platelet-derived ex vivo systems can be used to demonstrate PI3Kb-mediated target engagement in patients receiving selective inhibitors. 11 This phase 1, first-in-human study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of the selective PI3Kb inhibitor SAR260301 (clinicaltrials. gov identifier NCT01673737).…”