title: Lactate and choline metabolites detected in vitro by nuclear magnetic resonance spectroscopy are potential metabolic biomarkers for PI3K inhibition in pediatric glioblastoma.
abstract: The phosphoinositide 3-kinase (PI3K) pathway is believed to be of key importance in pediatric glioblastoma. Novel inhibitors of the PI3K pathway are being developed and are entering clinical trials. Our aim is to identify potential non-invasive biomarkers of PI3K signaling pathway inhibition in pediatric glioblastoma using in vitro nuclear magnetic resonance (NMR) spectroscopy, to aid identification of target inhibition and therapeutic response in early phase clinical trials of PI3K inhibitors in childhood cancer. Treatment of SF188 and KNS42 human pediatric glioblastoma cell lines with the dual pan-Class I PI3K/mTOR inhibitor PI-103, inhibited the PI3K signaling pathway and resulted in a decrease in phosphocholine (PC), total choline (tCho) and lactate levels (p<0.02) as detected by phosphorus (31P)- and proton (1H)-NMR. Similar changes were also detected using the pan-Class I PI3K inhibitor GDC-0941 which lacks significant mTOR activity and is entering Phase II clinical trials. In contrast, the DNA damaging agent temozolomide (TMZ), which is used as current frontline therapy in the treatment of glioblastoma postoperatively (in combination with radiotherapy), increased PC, glycerophosphocholine (GPC) and tCho levels (p<0.04). PI-103-induced NMR changes were associated with alterations in protein expression levels of regulatory enzymes involved in glucose and choline metabolism including GLUT1, HK2, LDHA and CHKA. Our results show that by using NMR we can detect distinct biomarkers following PI3K pathway inhibition compared to treatment with the DNA-damaging anti-cancer agent TMZ. This is the first study reporting that lactate and choline metabolites are potential non-invasive biomarkers for monitoring response to PI3K pathway inhibitors in pediatric glioblastoma.
authors.affiliation: Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Nada M S
authors.initials: NM
authors.lastname: Al-Saffar
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Division of Cancer Therapeutics, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Division of Clinical Studies. The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Lynley V
authors.initials: LV
authors.lastname: Marshall
authors.affiliation: Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: L Elizabeth
authors.initials: LE
authors.lastname: Jackson
authors.affiliation: Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Geetha
authors.initials: G
authors.lastname: Balarajah
authors.affiliation: Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Division of Imaging Sciences and Biomedical Engineering, King's College London, St Thomas' Hospital, London, United Kingdom.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Eykyn
authors.affiliation: Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Alice
authors.initials: A
authors.lastname: Agliano
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clarke
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Division of Cancer Therapeutics, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; 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: Division of Cancer Therapeutics, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Division of Clinical Studies. The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Andrew D J
authors.initials: AD
authors.lastname: Pearson
authors.affiliation: Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leach
mesh_terms: D045744:Cell Line, Tumor; D002794:Choline / Q000378:metabolism*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000201:enzymology* / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D019344:Lactic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
chemical_list: D019344:Lactic Acid; D019869:Phosphatidylinositol 3-Kinases; D002794:Choline
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