title: Response of Merkel cell polyomavirus-positive merkel cell carcinoma xenografts to a survivin inhibitor.
abstract: Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer associated with high mortality. Merkel cell polyomavirus (MCV), discovered in 2008, is associated with ~80% of MCC. The MCV large tumor (LT) oncoprotein upregulates the cellular oncoprotein survivin through its conserved retinoblastoma protein-binding motif. We confirm here that YM155, a survivin suppressor, is cytotoxic to MCV-positive MCC cells in vitro at nanomolar levels. Mouse survival was significantly improved for NOD-Scid-Gamma mice treated with YM155 in a dose and duration dependent manner for 3 of 4 MCV-positive MCC xenografts. One MCV-positive MCC xenograft (MS-1) failed to significantly respond to YM155, which corresponds with in vitro dose-response activity. Combination treatment of YM155 with other chemotherapeutics resulted in additive but not synergistic cell killing of MCC cell lines in vitro. These results suggest that survivin targeting is a promising therapeutic approach for most but not all MCV-positive MCCs.
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Lindsay R
authors.initials: LR
authors.lastname: Dresang
authors.forename: Anna
authors.initials: A
authors.lastname: Guastafierro
authors.forename: Reety
authors.initials: R
authors.lastname: Arora
authors.forename: Daniel
authors.initials: D
authors.lastname: Normolle
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chang
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Moore
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059965:Merkel cell polyomavirus / Q000235:genetics*; D051379:Mice; D009285:Naphthoquinones / Q000008:administration & dosage / Q000494:pharmacology; D009362:Neoplasm Metastasis; D027601:Polyomavirus Infections / Q000150:complications; D000077022:Survivin; D047368:Tumor Burden / Q000187:drug effects; D014412:Tumor Virus Infections / Q000150:complications; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium