title: Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment.
abstract: Multiple myeloma (MM), a blood cancer characterized by the uncontrolled proliferation of plasma cells, remains incurable by current therapy. Notch signaling has been implicated in the growth and chemoresistance of various cancer types including MM, and therefore we hypothesized that targeting the Notch pathway could be beneficial for the treatment of this disease. Here, we report an anti-tumor effect of Notch/γ-secretase inhibitor RO4929097 in a pre-clinical model of MM. We demonstrate that this effect was associated with decreased angiogenesis and significant down-regulation of TGF-β1. In addition, we also show that treatment with RO4929097 results in decreased number and functional activity of osteoclasts. Taken together, our data indicate that targeting Notch may be considered as a new strategy to be tested for MM therapy.
authors.affiliation: a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pisklakova
authors.affiliation: a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA.|b The Wistar Institute , Philadelphia , PA , USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Grigson
authors.affiliation: a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Ozerova
authors.affiliation: a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.affiliation: a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA.|b The Wistar Institute , Philadelphia , PA , USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Nefedova
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D001552:Benzazepines; D051880:Receptors, Notch; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons
keywords: Gamma-secretase inhibitor; RO4929097; TGF-β1; multiple myeloma; notch inhibitor; notch signaling; osteoclasts