Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF

Abstract

RationaleIdiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal of all fibrotic conditions with no curative therapies. Common pathomechanisms between IPF and cancer are increasingly recognised, including dysfunctional pan-PI3 kinase (PI3K) signalling as a driver of aberrant proliferative responses. GSK2126458 is a novel, potent, PI3K/mammalian target of rapamycin (mTOR) inhibitor which has recently completed phase I trials in the oncology setting. Our aim was to establish a scientific and dosing framework for PI3K inhibition with this agent in IPF at a clinically developable dose.MethodsWe explored evidence for pathway signalling in IPF lung tissue and examined the potency of GSK2126458 in fibroblast functional assays and precision-cut IPF lung tissue. We further explored the potential of IPF patient-derived bronchoalveolar lavage (BAL) cells to serve as pharmacodynamic biosensors to monitor GSK2126458 target engagement within the lung.ResultsWe provide evidence for PI3K pathway activation in fibrotic foci, the cardinal lesions in IPF. GSK2126458 inhibited PI3K signalling and functional responses in IPF-derived lung fibroblasts, inhibiting Akt phosphorylation in IPF lung tissue and BAL derived cells with comparable potency. Integration of these data with GSK2126458 pharmacokinetic data from clinical trials in cancer enabled modelling of an optimal dosing regimen for patients with IPF.ConclusionsOur data define PI3K as a promising therapeutic target in IPF and provide a scientific and dosing framework for progressing GSK2126458 to clinical testing in this disease setting. A proof-of-mechanism trial of this agent is currently underway.Trial registration numberNCT01725139, pre-clinical.

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

“…Using a murine model, Chung et al (22) demonstrated that rapamycin treatment reduced inflammatory cytokine expression, extracellular matrix production and senescence in type II pneumocytes, and that rapamycin protected against radiation-induced pulmonary fibrosis. Phosphoinositide 3-kinase (PI3K) was reported as a promising therapeutic target for idiopathic pulmonary fibrosis (23). Rapamycin may increase connective tissue growth factor expression in lung fibroblasts by regulating the PI3K signaling pathway (24).…”

Idiopathic Pulmonary Fibrosis: Molecular Endotypes of Fibrosis Stratifying Existing and Emerging Therapies

“…The use of pan-PI3 kinase (PI3K)/mammalian target of rapamycin (mTOR) in IPF is an example of the potential role of existing oncology drugs as novel therapeutic agents in IPF patients. GSK2126458 inhibited PI3K signalling and functional responses in IPF-derived lung fibroblasts, through blocking Akt phosphorylation in cells derived from tissue and BAL of IPF patients [119]. A double-blind, placebo-controlled, parallel study of GSK2126458, a PI3K/mTOR inhibitor, has been completed (NCT01725139, waiting for results).…”

Repositioning compounds from cancer drug discovery to IPF: PI3K inhibition

“…Mercer et al 13 propose the novel antitumour agent GSK2126458, a pan-class I phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor, as a therapeutic agent for IPF. Following activation via tyrosine kinases and/or G protein-coupled receptors, PI3Ks generate the lipid second messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ), which coordinates localisation of multiple signalling molecules with a Pleckstrin homology domain, most importantly Akt, at the plasma membrane 14.…”

“…The integration of these two data sets, the PK data from the ongoing trial and the gathered in vitro data using the described functional readouts, is a major strength of this study as it allowed the authors to deduce a dosing framework, which should ensure safe and effective target engagement in the lungs of patients with IPF. Hereby, Mercer et al 13 not only paved the way for an IPF proof-of-mechanism study (NCT01725139), but provided a generally valid roadmap for how to evaluate the potential of drug repositioning at the early clinical trial stage, and the authors should be lauded for this effort.…”

“…In this context, the authors suggest the use of cells obtained by bronchoalveolar lavage, which mostly consist of alveolar macrophages, as a relatively easily accessible pharmacodynamic biosensor 13. Even if (myo-)fibroblasts and bronchial/alveolar epithelial cells, and not macrophages, represented the main target cell type for IPF pathogenetic research approaches in the past, this appears as a compelling way to assess whether a drug reached the target tissue and affected resident lung cells.…”