Survivin Is a Therapeutic Target in Merkel Cell Carcinoma

A targeted therapy for a virus-induced cancer involves blockade of the cellular oncoprotein survivin. 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. Merkel cell polyomavirus (MCV) causes ~80% of primary and metastatic Merkel cell carcinomas (MCCs). By comparing digital transcriptome subtraction deep-sequencing profiles, we found that transcripts of the cellular survivin oncoprotein [BIRC5a (baculoviral inhibitor of apoptosis repeat-containing 5)] were up-regulated sevenfold in virus-positive compared to virus-negative MCC tumors. Knockdown of MCV large T antigen in MCV-positive MCC cell lines decreased survivin mRNA and protein expression. Exogenously expressed MCV large T antigen increased survivin protein expression in non-MCC primary cells. This required an intact retinoblastoma protein–targeting domain that activated survivin gene transcription as well as expression of other G1-S–phase proteins including E2F1 and cyclin E. Survivin expression is critical to the survival of MCV-positive MCC cells. A small-molecule survivin inhibitor, YM155, potently and selectively initiates irreversible, nonapoptotic, programmed MCV-positive MCC cell death. Of 1360 other chemotherapeutic and pharmacologically active compounds screened in vitro, only bortezomib (Velcade) was found to be similarly potent, but was not selective in killing MCV-positive MCC cells. YM155 halted the growth of MCV-positive MCC xenograft tumors and was nontoxic in mice, whereas bortezomib was not active in vivo and mice displayed serious morbidity. Xenograft tumors resumed growth once YM155 treatment was stopped, suggesting that YM155 may be cytostatic rather than cytotoxic in vivo. Identifying the cellular pathways, such as those involving survivin, that are targeted by tumor viruses can lead to rapid and rational identification of drug candidates for treating virus-induced cancers.