title: SNS01-T modulation of eIF5A inhibits B-cell cancer progression and synergizes with bortezomib and lenalidomide.
abstract: The high rates of recurrence and low median survival in many B-cell cancers highlight a need for new targeted therapeutic modalities. In dividing cells, eukaryotic translation initiation factor 5A (eIF5A) is hypusinated and involved in regulation of protein synthesis and proliferation, whereas the non-hypusinated form of eIF5A is a potent inducer of cell death in malignant cells. Here, we demonstrate the potential of modulating eIF5A expression as a novel approach to treating B-cell cancers. SNS01-T is a nonviral polyethylenimine-based nanoparticle, designed to induce apoptosis selectively in B-cell cancers by small interfering RNA-mediated suppression of hypusinated eIF5A and plasmid-based overexpression of a non-hypusinable eIF5A mutant. In this study, we show that SNS01-T is preferentially taken up by malignant B cells, inhibits tumor growth in multiple animal models of B-cell cancers without damaging normal tissues, and synergizes with the current therapies bortezomib and lenalidomide to inhibit tumor progression. The results collectively demonstrate the potential of SNS01-T as a novel therapeutic for treatment of a diverse range of B-cell malignancies.
authors.affiliation: Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Francis
authors.affiliation: Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Taylor
authors.affiliation: Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Terence
authors.initials: T
authors.lastname: Tang
authors.affiliation: Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Zhongda
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Qifa
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Senesco Technologies, Bridgewater, New Jersey, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Dondero
authors.affiliation: 1] Department of Biology, University of Waterloo, Waterloo, Ontario, Canada [2] Senesco Technologies, Bridgewater, New Jersey, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Thompson
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D000077269:Lenalidomide; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry* / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors*; D011094:Polyethyleneimine / Q000737:chemistry; D011719:Pyrazines / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D001897:Boronic Acids; D000069286:Bortezomib; D000077269:Lenalidomide; D010448:Peptide Initiation Factors; D011094:Polyethyleneimine; D011719:Pyrazines; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D013792:Thalidomide; D000097574:Eukaryotic Translation Initiation Factor 5A