title: Heat shock protein 90 is a promising target for effective growth inhibition             of gastrointestinal neuroendocrine tumors.
abstract: Treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NET) is still             unsatisfactory and innovative therapeutic approaches are urgently needed. Heat             shock protein 90 (Hsp90) is overexpressed in a wide range of tumor types and is             an emerging target for the treatment of cancer. However, the potential activity             of Hsp90 inhibitors in GEP-NET has not yet been investigated. We studied the antineoplastic             activity of the Hsp90 inhibitor IPI-504 on GEP‑NET cells, and characterized its             mechanism of action. In human insulinoma (CM) and pancreatic carcinoid (BON) cells             IPI-504 induced a dose-dependent growth inhibition by almost 70%. The antiproliferative             effect of IPI-504 correlated with a reduction in protein levels of the IGF-1 receptor.             Additionally, several proteins of the PI3K/AKT/mTOR pathway, downstream of IGF-1             receptor activation in GEP-NETs, were downregulated as a consequence of Hsp90             inhibition. Combination treatment of IPI-504 with mTOR- or AKT-inhibitors led             to additive antiproliferative effects. In addition, effects of IGF-1 receptor             tyrosine kinase inhibition were strongly enhanced by IPI-504. Cancer gene expression             profiling and FACS analysis revealed that IPI-504 antiproliferative effects were             due to both induction of cell cycle arrest and apoptosis. A modified chick chorioallantoic             membrane (CAM) assay confirmed the antineoplastic activity of IPI-504 in GEP-NETs             in vivo. In conclusion, this study showed that Hsp90 inhibition may be an attractive             target for innovative GEP-NET treatment alone or in combination with either IGF-1R             or mTOR inhibitors.
authors.affiliation: Department of Physiology, Charité - Universitaetsmedizin Berlin,                     Campus Benjamin Franklin, Thielallee 71, D-14195 Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Gloesenkamp
authors.forename: Bianca
authors.initials: B
authors.lastname: Nitzsche
authors.forename: Alice R
authors.initials: AR
authors.lastname: Lim
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Normant
authors.forename: Evan
authors.initials: E
authors.lastname: Vosburgh
authors.forename: Mark
authors.initials: M
authors.lastname: Schrader
authors.forename: Matthias
authors.initials: M
authors.lastname: Ocker
authors.forename: Hans
authors.initials: H
authors.lastname: Scherübl
authors.forename: Michael
authors.initials: M
authors.lastname: Höpfner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; C112765:tanespimycin; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases