RT Journal Article
SR Electronic
T1 Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF
JF Thorax
JO Thorax
FD BMJ Publishing Group Ltd and British Thoracic Society
SP 701
OP 711
DO 10.1136/thoraxjnl-2015-207429
VO 71
IS 8
A1 Paul F Mercer
A1 Hannah V Woodcock
A1 Jessica D Eley
A1 Manuela Platé
A1 Michal G Sulikowski
A1 Pascal F Durrenberger
A1 Linda Franklin
A1 Carmel B Nanthakumar
A1 Yim Man
A1 Federica Genovese
A1 Robin J McAnulty
A1 Shuying Yang
A1 Toby M Maher
A1 Andrew G Nicholson
A1 Andy D Blanchard
A1 Richard P Marshall
A1 Pauline T Lukey
A1 Rachel C Chambers
YR 2016
UL http://thorax.bmj.com/content/71/8/701.abstract
AB Rationale Idiopathic 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.Methods We 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.Results We 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.Conclusions Our 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 number NCT01725139, pre-clinical.