title: Upregulation of Key Molecules for Targeted Imaging and Therapy.
abstract: Targeted diagnosis and therapy enable precise tumor detection and treatment. Successful examples for precise tumor targeting are diagnostic and therapeutic radioligands. However, patients with tumors expressing low levels of the relevant molecular targets are deemed ineligible for such targeted approaches.
  
  
  METHODS
  We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr2). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo.
  
  
  RESULTS
  We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr2on transcriptional, translational, and functional levels in a time- and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr2upregulation improved the tumor-to-background and tumor-to-kidney ratios, which are the key determinants of successful sstr2-targeted imaging and radiopeptide therapy.
  
  
  CONCLUSIONS
  We present an approach that uses epigenetic modifiers to improve sstr2targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates.
authors.affiliation: Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.|Clinical Radiopharmacy, Department of Clinical Research, University Hospital Bern, Bern, Switzerland.
authors.forename: Vincent F
authors.initials: VF
authors.lastname: Taelman
authors.affiliation: Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.|Clinical Radiopharmacy, Department of Clinical Research, University Hospital Bern, Bern, Switzerland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Radojewski
authors.affiliation: Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.|Clinical Radiopharmacy, Department of Clinical Research, University Hospital Bern, Bern, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Marincek
authors.affiliation: Pituitary Center, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: Anat
authors.initials: A
authors.lastname: Ben-Shlomo
authors.affiliation: Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.|Clinical Radiopharmacy, Department of Clinical Research, University Hospital Bern, Bern, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Grotzky
authors.affiliation: Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.|Clinical Radiopharmacy, Department of Clinical Research, University Hospital Bern, Bern, Switzerland.
authors.forename: Cristina I
authors.initials: CI
authors.lastname: Olariu
authors.affiliation: Institute of Pathology, University Bern, Bern, Switzerland.
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.affiliation: Division of Diabetes, Endocrinology, Nutritional Medicine & Metabolism, University Hospital and Inselspital, Bern, Switzerland; and.
authors.forename: Christoph
authors.initials: C
authors.lastname: Stettler
authors.affiliation: Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.|Clinical Radiopharmacy, Department of Clinical Research, University Hospital Bern, Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krause
authors.affiliation: Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.|Clinical Radiopharmacy, Department of Clinical Research, University Hospital Bern, Bern, Switzerland.
authors.forename: Lorenz P
authors.initials: LP
authors.lastname: Meier
authors.affiliation: Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.|Clinical Radiopharmacy, Department of Clinical Research, University Hospital Bern, Bern, Switzerland.
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.affiliation: Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland m.a.walter@gmx.net.|Clinical Radiopharmacy, Department of Clinical Research, University Hospital Bern, Bern, Switzerland.|Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Walter
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D000077209:Decitabine; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D057089:Pathology, Molecular / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods; D017481:Receptors, Somatostatin / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D014408:Biomarkers, Tumor; D009942:Organometallic Compounds; D017481:Receptors, Somatostatin; C492049:Sstr2 protein, mouse; D000077209:Decitabine; C513399:gallium Ga 68 dotatate; D001374:Azacitidine
keywords: DOTATATE; DOTATOC; PRRT; molecular imaging; neuroendocrine tumors