Research ArticleCancer

Survivin Is a Therapeutic Target in Merkel Cell Carcinoma

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Science Translational Medicine  09 May 2012:
Vol. 4, Issue 133, pp. 133ra56
DOI: 10.1126/scitranslmed.3003713

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Targeting a Hijacked Protein

Some have expressed disappointment that the Human Genome Project has not delivered more on its promise to find causes and cures for diseases such as cancer. Until recently, Merkel cell carcinoma (MCC) had no known etiology and few treatment options beyond surgery and irradiation. MCC, an aggressive nonmelanotic human skin cancer, is most commonly found in elderly and immunosuppressed populations, suggesting a possible viral cause. In 2008, a transcriptomic technology based on genomics revealed a new virus, Merkel cell polyomavirus (MCV), that causes ~80% of MCC.

In a new study, Arora et al. now identify the molecular pathway that is activated in MCC cells by this virus. When the authors deleted viral oncoproteins called T antigens expressed in MCV-infected MCC cells, they found that a key cellular protein, survivin, also disappeared and the MCC cells died. Survivin mRNA expression is controlled by the MCV large T antigen, which binds to the cell cycle regulator retinoblastoma protein. Activation of the survivin gene by MCV was confirmed using the same transcriptome data set that was originally used to identify this virus. Survivin has been implicated in other cancers and is known to confer chemotherapy resistance on tumors. This cellular oncoprotein can be targeted by an imidazole small-molecule inhibitor called YM155 that has entered phase 2 trials for treating certain cancers. Arora et al. show that YM155 at nanomolar concentrations preferentially killed MCC cells infected with MCV. In contrast, of 1360 other compounds screened, only one other chemotherapeutic drug (bortezomib) showed similar potency. When human MCC tumors were grown in immunodeficient mice as xenografts, YM155 halted tumor growth and prolonged mouse survival during short-term treatment. These new findings demonstrate how genomic data can be applied to help identify the cause of a cancer and thus point the way to new targets that can be exploited therapeutically.

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