title: In vivo monitoring of the anti-angiogenic therapeutic effect of the pan-deacetylase inhibitor panobinostat by small animal PET in a mouse model of gastrointestinal cancers.
abstract: BACKGROUND
  Deacetylase inhibitors have recently been established as a novel therapeutic approach to solid and hematologic cancers and have also been demonstrated to possess anti-angiogenic properties. Although these compounds show a good efficacy in vitro and in vivo, no data on monitoring and predicting treatment response are currently available. We therefore investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on gastrointestinal cancer models and the suitability of 2-[(18)F]FGlc-RGD as a specific agent for imaging integrin αvβ3 expression during tumor angiogenesis using small animal positron emission tomography (PET).
  
  
  METHODS
  The effect of panobinostat on cell viability in vitro was assessed with a label-free impedance based real-time analysis. Nude mice bearing HT29 and HepG2 tumors were treated with daily i.p. injections of 10mg/kg panobinostat for 4 weeks. During this time, tumor size was determined with a calliper and mice were repeatedly subjected to PET imaging. Tumor tissues were analyzed immunohistochemically with a focus on proliferation and endothelial cell markers (Ki-67, Meca-32) and by Western blot applying specific markers of apoptosis.
  
  
  RESULTS
  In vitro, panobinostat inhibited the proliferation of HepG2 and HT29 cells. Contrary to the situation in HepG2 tumors in vivo, where panobinostat treatment is known to reduce proliferation and vascularization resulting in a decreased tumor growth, HT29 tumors did not show any effect on these parameters. We demonstrated by Western blotting, that panobinostat induced apoptosis in HT29 tumors in vivo. Longitudinal PET imaging studies in HepG2 tumor-bearing mice using 2-[(18)F]FGlc-RGD demonstrated that the standard uptake value (SUVmax) in HepG2 tumors was significantly decreased by 39% at day 7 after treatment. The comparative PET study using HT29 tumor-bearing animals did not reveal any response of the tumors to panobinostat treatment.
  
  
  CONCLUSIONS
  Small-animal PET imaging using 2-[(18)F]FGlc-RGD was successfully applied to the non-invasive monitoring of the HepG2-tumor response to panobinostat in nude mice early after begin of treatment. Thus, PET imaging of angiogenesis using 2-[(18)F]FGlc-RGD could be a valuable tool to monitor panobinostat therapy in further preclinical studies.
  
  
  CONCLUSIONS
  When successfully translated to the clinical surrounding, PET imaging of angiogenesis could therefore facilitate therapy planning and monitoring of therapy success with panobinostat in hepatocellular carcinoma.
authors.affiliation: Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University (FAU), Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Maschauer
authors.affiliation: Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Gahr
authors.affiliation: Experimental Tumorpathology, Department of Pathology, Friedrich Alexander University (FAU), Erlangen, Germany.
authors.forename: Muktheshwar
authors.initials: M
authors.lastname: Gandesiri
authors.affiliation: Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University (FAU), Erlangen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Tripal
authors.affiliation: Experimental Tumorpathology, Department of Pathology, Friedrich Alexander University (FAU), Erlangen, Germany.
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.affiliation: Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University (FAU), Erlangen, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Kuwert
authors.affiliation: Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany. Electronic address: matthias.ocker@bayer.com.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ocker
authors.affiliation: Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University (FAU), Erlangen, Germany. Electronic address: olaf.prante@uk-erlangen.de.
authors.forename: Olaf
authors.initials: O
authors.lastname: Prante
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000077767:Panobinostat; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D049268:Positron-Emission Tomography; D011379:Prognosis; D059748:Proteolysis / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3
keywords: Colon cancer; Hepatocellular carcinoma; Histone deacetylase inhibitor; Panobinostat; Positron emission tomography; RGD peptide