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

Autor:	Mercer PF; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK., Woodcock HV; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK., Eley JD; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK., Platé M; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK., Sulikowski MG; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK., Durrenberger PF; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK., Franklin L; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK., Nanthakumar CB; Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK., Man Y; Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK., Genovese F; Nordic Bioscience, Herlev, Denmark., McAnulty RJ; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK., Yang S; Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK., Maher TM; NIHR Respiratory Biomedical Research Unit, Royal Brompton Hospital, London, UK., Nicholson AG; NIHR Respiratory Biomedical Research Unit, Royal Brompton Hospital, London, UK., Blanchard AD; Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK., Marshall RP; Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK., Lukey PT; Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK., Chambers RC; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK.
Jazyk:	angličtina
Zdroj:	Thorax [Thorax] 2016 Aug; Vol. 71 (8), pp. 701-11. Date of Electronic Publication: 2016 Apr 21.
DOI:	10.1136/thoraxjnl-2015-207429
Abstrakt:	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. (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
Databáze:	MEDLINE
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