title: Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma.
abstract: BACKGROUND
  Dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET) imaging using the standard tracer, 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and the thymidine analog, 3'-deoxy-3'-[(18)F] fluorothymidine (FLT).
  
  
  METHODS
  The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects.
  
  
  RESULTS
  SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In vivo, both FDG-PET and FLT-PET discriminated sensitive from resistant lymphoma, as indicated by a significant reduction of tumor-to-background ratios on day 7 in treated SU-DHL-1 lymphoma-bearing animals compared with the control group, but not in animals with Karpas299 xenografts. Imaging results correlated with a marked decrease in the proliferation marker Ki67, and a slight increase in the apoptotic marker, cleaved caspase 3, as revealed by immunostaining of explanted lymphoma tissue.
  
  
  CONCLUSIONS
  Dual PI3K/mTOR inhibition using BGT226 is effective in ALK-positive anaplastic large cell lymphoma and can be monitored with both FDG-PET and FLT-PET early on in the course of therapy.
authors.affiliation: III Medical Department, Technische Universität München, Munich, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Graf
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.
authors.forename: Zhoulei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany ; Department of Nuclear Medicine, Universitätsklinikum Würzburg, Würzburg, Germany.
authors.forename: Ken
authors.initials: K
authors.lastname: Herrmann
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weh
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Slawska
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.affiliation: III Medical Department, Technische Universität München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany ; Department of Nuclear Medicine, Universitätsklinikum Würzburg, Würzburg, Germany.
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Buck
authors.affiliation: III Medical Department, Technische Universität München, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Dechow
authors.affiliation: III Medical Department, Technische Universität München, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keller
keywords: inhibition; lymphoma; mammalian target of rapamycin; phosphatidylinositol-3-kinase; positron emission tomography