title: Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas.
abstract: OBJECTIVE
  Novel therapeutic approaches are needed to improve the postoperative management of residual nonfunctioning pituitary adenomas (NFPA), given their high relapse rate. Here, we evaluated the antitumor efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in the only available model of spontaneous NFPAs (MENX rats).
  
  
  METHODS
  Organotypic cultures of rat primary NFPAs were incubated with NVP-BEZ235 and assessed for cell viability, proliferation, apoptosis, and PI3K/mTOR inhibition. NVP-BEZ235, or placebo, was administered to MENX rats and tumor response was monitored noninvasively by diffusion weighted-magnetic resonance imaging (DW-MRI). Following treatment, tumor tissues were investigated for cell proliferation, apoptosis, and PI3K/mTOR inhibition. Genes mediating the cytotoxic activity of NVP-BEZ235 were identified by gene-expression profiling. Among them, Defb1, encoding beta-defensin 1, was further studied for its role in pituitary cells and in human pancreatic neuroendocrine tumor (NET) cells.
  
  
  RESULTS
  NVP-BEZ235 showed antiproliferative and pro-cell death activities against NFPAs both in vitro and in vivo, and the response to the drug correlated with inhibition of the PI3K pathway. DW-MRI identified early functional changes (decreased cellularity) in the adenomas before their size was affected and emerged as a useful modality to assess therapy response. The cytotoxic effect of PI3K/mTOR blockade in NFPA was mediated by several genes, including Defb1. NVP-BEZ235 treatment induced Defb1 expression in NFPAs in vitro and in vivo, and in pancreatic NET cells. High Defb1 levels sensitized NET cells to PI3K/mTOR inhibition.
  
  
  CONCLUSIONS
  Our findings provide rationale for clinical investigation of PI3K/mTOR inhibition in NFPAs and identify novel effectors of PI3K-mediated neuroendocrine cell survival.
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Misu
authors.initials: M
authors.lastname: Lee
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Wiedemann
authors.affiliation: Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gross
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Leinhäuser
authors.affiliation: Department of Medicine, Imperial College, London, United Kingdom.
authors.forename: Federico
authors.initials: F
authors.lastname: Roncaroli
authors.affiliation: Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Rickmer
authors.initials: R
authors.lastname: Braren
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany. Natalia.pellegata@helmholtz-muenchen.de.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Pellegata
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D023082:Defensins / Q000096:biosynthesis; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010911:Pituitary Neoplasms / Q000473:pathology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011922:Rats, Mutant Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023083:beta-Defensins / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; C406407:DEFB1 protein, human; C478968:Defb1 protein, rat; D023082:Defensins; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D023083:beta-Defensins; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib