RT Journal Article
SR Electronic
T1 The effect of a novel phosphoinositide 3-kinase δ inhibitor (PI3Kδ), GSK2269557, on potential biomarkers measured from the lungs of healthy male smokers
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 4859
VO 42
IS Suppl 57
A1 Sally Worsley
A1 Augustin Amour
A1 Amanda Deans
A1 Iain McSherry
A1 Mark Lennon
A1 Sylvia Fung
A1 Nicole Hamblin
A1 Phillip Hawkins
A1 Edith M. Hessel
YR 2013
UL http://erj.ersjournals.com/content/42/Suppl_57/4859.abstract
AB Phosphatidylinositol (4,5)-bisphosphate (PIP2) is converted by PI3Kδ into Phosphatidylinositol (3,4,5)-trisphosphate (PIP3). This activates cellular functions including proliferation and differentiation.PI3Kδ, which is inhibited by GSK2269557, is a promising therapeutic target for respiratory disease.Aim: To identify markers of PI3Kδ target engagement.Methods: In one part of a single centre, randomized, double blind, placebo controlled phase I study, 2 cohorts of healthy male smokers were given active dose and placebo in a cross over design (ERS 851005). Sputum or bronchioaveolar lavage (BAL) was taken 3 hours post dosing. In the sputum cohort, PIP3 levels were measured and normalised by PIP2. In the BAL cohort, cell surface L- selectin (CD62L) and phosphorylated forkhead box 01 (p-FOXO1) were measured.Results: PIP3 levels in sputum were reduced by 20% & 23% at 400µg, 6400µg of GSK2269557 respectively [p<0.05].P-FOXO1: BAL cell expression showed a decrease in the active group in both macrophage and neutrophil cytoplasm [p<0.05] which is maintained in macrophages when pFOXO1 is normalised to total FOXO-1 [p<0.05].L-selectin: The proportion of cells with cell membrane associated L- selectin showed an increase of 48% for macrophages and 21% for neutrophils in the active groups compared with placebo [p<0.05].Conclusions: PIP3 is a suitable biomarker to demonstrate GSK2269557 target engagement, as indicated by reduced levels of PIP3 in GSK2269557 treated subjects. Downstream of PIP3, reduced levels of p-FOXO1 and increased L-selectin cell surface expression were consistent with PI3K inhibition and support the PIP3 results.