PMID- 27103349 OWN - NLM STAT- MEDLINE DCOM- 20170615 LR - 20220129 IS - 1468-3296 (Electronic) IS - 0040-6376 (Print) IS - 0040-6376 (Linking) VI - 71 IP - 8 DP - 2016 Aug TI - Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF. PG - 701-11 LID - 10.1136/thoraxjnl-2015-207429 [doi] 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. CI - 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/ FAU - Mercer, Paul F AU - Mercer PF AD - Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK. FAU - Woodcock, Hannah V AU - Woodcock HV AD - Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK. FAU - Eley, Jessica D AU - Eley JD AD - Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK. FAU - Plate, Manuela AU - Plate M AD - Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK. FAU - Sulikowski, Michal G AU - Sulikowski MG AD - Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK. FAU - Durrenberger, Pascal F AU - Durrenberger PF AD - Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK. FAU - Franklin, Linda AU - Franklin L AD - Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK. FAU - Nanthakumar, Carmel B AU - Nanthakumar CB AD - Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK. FAU - Man, Yim AU - Man Y AD - Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK. FAU - Genovese, Federica AU - Genovese F AD - Nordic Bioscience, Herlev, Denmark. FAU - McAnulty, Robin J AU - McAnulty RJ AD - Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK. FAU - Yang, Shuying AU - Yang S AD - Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK. FAU - Maher, Toby M AU - Maher TM AD - NIHR Respiratory Biomedical Research Unit, Royal Brompton Hospital, London, UK. FAU - Nicholson, Andrew G AU - Nicholson AG AD - NIHR Respiratory Biomedical Research Unit, Royal Brompton Hospital, London, UK. FAU - Blanchard, Andy D AU - Blanchard AD AD - Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK. FAU - Marshall, Richard P AU - Marshall RP AD - Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK. FAU - Lukey, Pauline T AU - Lukey PT AD - Department of Fibrosis DPU, Respiratory TA, GlaxoSmithKline, Stevenage, UK. FAU - Chambers, Rachel C AU - Chambers RC AD - Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London, London, UK. LA - eng SI - ClinicalTrials.gov/NCT01725139 GR - G1000440/MRC_/Medical Research Council/United Kingdom GR - MR/K024078/1/MRC_/Medical Research Council/United Kingdom GR - BB_/Biotechnology and Biological Sciences Research Council/United Kingdom PT - Journal Article DEP - 20160421 PL - England TA - Thorax JT - Thorax JID - 0417353 RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridazines) RN - 0 (Quinolines) RN - 0 (Sulfonamides) RN - 1X8F5A3NA0 (omipalisib) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM CIN - Thorax. 2016 Aug;71(8):675-6. PMID: 27307018 MH - Cell Proliferation MH - Clinical Trials as Topic MH - Fibroblasts/metabolism MH - Humans MH - Idiopathic Pulmonary Fibrosis/*drug therapy/pathology MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Protein Kinase Inhibitors/*therapeutic use MH - Pyridazines MH - Quinolines/*therapeutic use MH - Signal Transduction MH - Sulfonamides/*therapeutic use MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors MH - Treatment Outcome PMC - PMC4975851 OTO - NOTNLM OT - Idiopathic pulmonary fibrosis EDAT- 2016/04/23 06:00 MHDA- 2017/06/16 06:00 PMCR- 2016/08/06 CRDT- 2016/04/23 06:00 PHST- 2015/06/15 00:00 [received] PHST- 2016/03/15 00:00 [accepted] PHST- 2016/04/23 06:00 [entrez] PHST- 2016/04/23 06:00 [pubmed] PHST- 2017/06/16 06:00 [medline] PHST- 2016/08/06 00:00 [pmc-release] AID - thoraxjnl-2015-207429 [pii] AID - 10.1136/thoraxjnl-2015-207429 [doi] PST - ppublish SO - Thorax. 2016 Aug;71(8):701-11. doi: 10.1136/thoraxjnl-2015-207429. Epub 2016 Apr 21.