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



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.



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.



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.



NCT01725139, pre-clinical.
Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK.
Paul F
PF
Mercer
Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK.
Hannah V
HV
Woodcock
Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK.
Jessica D
JD
Eley
Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK.
Manuela
M
Platé
Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK.
Michal G
MG
Sulikowski
Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK.
Pascal F
PF
Durrenberger
Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK.
Linda
L
Franklin
Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK.
Carmel B
CB
Nanthakumar
Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK.
Yim
Y
Man
Nordic Bioscience, Herlev, Denmark.
Federica
F
Genovese
Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK.
Robin J
RJ
McAnulty
Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK.
Shuying
S
Yang
NIHR Respiratory Biomedical Research Unit, Royal Brompton Hospital, London, UK.
Toby M
TM
Maher
NIHR Respiratory Biomedical Research Unit, Royal Brompton Hospital, London, UK.
Andrew G
AG
Nicholson
Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK.
Andy D
AD
Blanchard
Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK.
Richard P
RP
Marshall
Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK.
Pauline T
PT
Lukey
Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK.
Rachel C
RC
Chambers
D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011724:Pyridazines; D011804:Quinolines / Q000627:therapeutic use*; D015398:Signal Transduction; D013449:Sulfonamides / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D000096926:Benzenesulfonamides
D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011804:Quinolines; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C561454:omipalisib; D000096926:Benzenesulfonamides
Idiopathic pulmonary fibrosis