Response of Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma Xenografts to a Survivin Inhibitor |
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| Authors: | Lindsay R Dresang Anna Guastafierro Reety Arora Daniel Normolle Yuan Chang Patrick S Moore |
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| Institution: | 1. Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.; 2. Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, GKVK Campus, Bangalore, India.; 3. Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.; University of Southern California Keck School of Medicine, United States of America, |
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| 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. |
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