title: Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecologic Malignancies.
abstract: AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study's primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and (18)F-FDG PET markers of glucose metabolism in tumor tissue to determine whether (18)F-FDG PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken.
  
  
  METHODS
  Twelve patients were enrolled in 3 cohorts; all underwent dynamic (18)F-FDG PET scans and serial pharmacokinetic sampling at baseline, week 2, and week 4 with tumor biopsies before treatment and at week 4. Response was evaluated by RECIST v1.1 and Gynecologic Cancer Intergroup criteria. Biopsy samples were analyzed for mutations and protein expression.
  
  
  RESULTS
  GSK2141795 did not significantly influence blood glucose levels. No dose-response relationship was observed between GSK2141795 pharmacokinetics and (18)F-FDG PET pharmacodynamic measures; however, an exposure-response relationship was seen between maximum drug concentrations and maximal decrease in (18)F-FDG uptake in the best-responding tumor. This relationship also held for pharmacokinetic parameters of exposure and 1,5-anhydroglucitol (a systemic measure of glucose metabolism). Phospho-AKT upregulation at week 4 in biopsies confirmed AKT inhibition by GSK2141795. Single-agent activity was observed with a clinical benefit rate of 27% (3/11) and 30% (3/10) CA125 response in the study's platinum-resistant ovarian patients. AKT pathway activation by PIK3CA/PIK3R1 mutation did not correlate with clinical activity, whereas RAS/RAF pathway mutations did segregate with resistance to AKT inhibition.
  
  
  CONCLUSIONS
  GSK2141795 demonstrated an exposure-response relationship with decreased (18)F-FDG uptake and is active and tolerable. This study's design integrating (18)F-FDG PET, pharmacokinetics, and biomarker analyses demonstrates the potential for clinical development for personalized treatment.
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom h.gungor@imperial.ac.uk.
authors.forename: Hatice
authors.initials: H
authors.lastname: Gungor
authors.affiliation: Imanova Centre for Imaging Sciences (formerly GSK Clinical Imaging Centre), Hammersmith Hospital, London, United Kingdom.
authors.forename: Azeem
authors.initials: A
authors.lastname: Saleem
authors.affiliation: Department of Radiology, Imperial College Healthcare NHS Trust, London, United Kingdom.
authors.forename: Syed
authors.initials: S
authors.lastname: Babar
authors.affiliation: Department of Histopathology, Imperial College London, London, United Kingdom.
authors.forename: Roberto
authors.initials: R
authors.lastname: Dina
authors.affiliation: Department of Histopathology, Imperial College London, London, United Kingdom.
authors.forename: Mona A
authors.initials: MA
authors.lastname: El-Bahrawy
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Ed
authors.initials: E
authors.lastname: Curry
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Nona
authors.initials: N
authors.lastname: Rama
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Chen
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Pickford
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Roshan
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Blagden
authors.affiliation: AVIESAN, Strategic Valorization, Paris, France.
authors.forename: Sabin
authors.initials: S
authors.lastname: Carme
authors.affiliation: Imanova Centre for Imaging Sciences (formerly GSK Clinical Imaging Centre), Hammersmith Hospital, London, United Kingdom.
authors.forename: Cristian
authors.initials: C
authors.lastname: Salinas
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania and Research Triangle Park, North Carolina; and.
authors.forename: Sam
authors.initials: S
authors.lastname: Madison
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania and Research Triangle Park, North Carolina; and.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Krachey
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania and Research Triangle Park, North Carolina; and.
authors.forename: Ademi
authors.initials: A
authors.lastname: Santiago-Walker
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania and Research Triangle Park, North Carolina; and.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Smith
authors.affiliation: MedImmune, AstraZeneca, Gaithersburg, Maryland.
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Morris
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Euan A
authors.initials: EA
authors.lastname: Stronach
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D003847:Deoxyglucose; D003959:Diamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D005833:Genital Neoplasms, Female / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D006801:Humans; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000235:genetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D001786:Blood Glucose; D003959:Diamines; C000595149:GSK2141795; D011720:Pyrazoles; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C006584:1,5-anhydroglucitol; D003847:Deoxyglucose; D051058:Oncogene Protein v-akt
keywords: AKT; FDG-PET; GSK2141795; imaging; ovarian cancer