title: Anti-angiogenic and anti-multiple myeloma effects of oprozomib (OPZ) alone and in combination with pomalidomide (Pom) and/or dexamethasone (Dex).
abstract: Oprozomib (OPZ or ONYX 0912) is an irreversible, orally administered proteasome inhibitor (PI) and an analog of carfilzomib. We set out to determine the anti-angiogenic effect of OPZ using the choriollantoic membrane/feather bud (CAM/FB) model and its anti-MM effects using MM xenograft models (LAGκ-1A, LAGλ-1). OPZ significantly reduced blood vessel formation, endothelial gene and protein expression using the CAM/FB assay. In vivo, we determined the anti-MM effects of OPZ, dexamethasone (Dex) and pomalidomide (Pom) and showed that the combinations of two drugs (OPZ+Dex or OPZ+Pom) showed marked anti-MM effects when compared to monotherapy. Pom+Dex and the triplicate combination (OPZ+Pom+Dex) showed more anti-MM effects when compared to the doublets of either OPZ+Dex or OPZ+Pom; continued treatment with all three drugs (OPZ+Pom+Dex) was superior when compared to Pom+Dex, in both MM xenograft models tested. These studies show that OPZ has anti-angiogenic effects, and that the combination of OPZ, Dex and Pom produces greater anti-MM effects in vivo when compared to any of the doublet combinations. These studies provide further support for clinical trials evaluating OPZ in combination with Pom and Dex.
authors.affiliation: Institute for Myeloma & Bone Cancer Research, West Hollywood, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Sanchez
authors.affiliation: Institute for Myeloma & Bone Cancer Research, West Hollywood, CA, USA.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Li
authors.affiliation: Institute for Myeloma & Bone Cancer Research, West Hollywood, CA, USA.
authors.forename: Cathy S
authors.initials: CS
authors.lastname: Wang
authors.affiliation: Institute for Myeloma & Bone Cancer Research, West Hollywood, CA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Tang
authors.affiliation: Institute for Myeloma & Bone Cancer Research, West Hollywood, CA, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Gillespie
authors.affiliation: Institute for Myeloma & Bone Cancer Research, West Hollywood, CA, USA.
authors.forename: Haiming
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute for Myeloma & Bone Cancer Research, West Hollywood, CA, USA. Electronic address: jberenson@imbcr.org.
authors.forename: James R
authors.initials: JR
authors.lastname: Berenson
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology*; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C554738:ONX 0912; D009842:Oligopeptides; D013792:Thalidomide; D003907:Dexamethasone; C467566:pomalidomide
keywords: Dexamethasone; Multiple myeloma; Oprozomib; Pomalidomide; Xenograft models