title: Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.
abstract: PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non-tumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a phase I dose-escalation clinical trial of pictilisib. Time- and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition. Mol Cancer Ther; 15(6); 1412-24. ©2016 AACR.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom. Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
authors.forename: Joo Ern
authors.initials: JE
authors.lastname: Ang
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rupinder
authors.initials: R
authors.lastname: Pandher
authors.affiliation: School of Physics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Joo Chew
authors.initials: JC
authors.lastname: Ang
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Yasmin J
authors.initials: YJ
authors.lastname: Asad
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Henley
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Alexis
authors.initials: A
authors.lastname: de Haven Brandon
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom. Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Baird
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Lori
authors.initials: L
authors.lastname: Friedman
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Mika
authors.initials: M
authors.lastname: Derynck
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom. Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom. Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom. Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. Florence.Raynaud@icr.ac.uk.
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D013058:Mass Spectrometry; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D014408:Biomarkers, Tumor; D007191:Indazoles; D013449:Sulfonamides; D051059:PTEN Phosphohydrolase