title: Preclinical efficacy of sepantronium bromide (YM155) in multiple myeloma is conferred by down regulation of Mcl-1.
abstract: The inhibitor-of-apoptosis family member survivin has been reported to inhibit apoptosis and regulate mitosis and cytokinesis. In multiple myeloma, survivin has been described to be involved in downstream sequelae of various therapeutic agents. We assessed 1093 samples from previously untreated patients, including two independent cohorts of 392 and 701 patients, respectively. Survivin expression was associated with cell proliferation, adverse prognostic markers, and inferior event-free and overall survival, supporting the evaluation of survivin as a therapeutic target in myeloma. The small molecule suppressant of survivin--YM155--is in clinical development for the treatment of solid tumors. YM155 potently inhibited proliferation and induced apoptosis in primary myeloma cells and cell lines. Gene expression and protein profiling revealed the critical roles of IL6/STAT3-signaling and the unfolded protein response in the efficacy of YM155. Both pathways converged to down regulate anti-apoptotic Mcl-1 in myeloma cells. Conversely, growth inhibition and apoptotic cell death by YM155 was rescued by ectopic expression of Mcl-1 but not survivin, identifying Mcl-1 as the pivotal downstream target of YM155 in multiple myeloma. Mcl-1 expression was likewise associated with adverse prognostic markers, and inferior survival. Our results strongly support the clinical evaluation of YM155 in patients with multiple myeloma.
authors.affiliation: Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Wagner
authors.affiliation: Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hose
authors.affiliation: Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Seckinger
authors.affiliation: Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Weiz
authors.affiliation: Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Meißner
authors.affiliation: INSERM U1040, Montpellier, France.
authors.forename: Thiery
authors.initials: T
authors.lastname: Rème
authors.affiliation: Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Breitkreutz
authors.affiliation: National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.affiliation: Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Alwin
authors.initials: A
authors.lastname: Krämer
authors.affiliation: INSERM U1040, Montpellier, France. CHU Montpellier, Institute of Research in Biotherapy, Montpellier, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Klein
authors.affiliation: Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Raab
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D015331:Cohort Studies; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D009101:Multiple Myeloma / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016019:Survival Analysis; D000077022:Survivin; D059467:Transcriptome; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009285:Naphthoquinones; D050796:STAT3 Transcription Factor; D000077022:Survivin; C523798:sepantronium