Merkel cell carcinoma (MCC) is an aggressive human skin cancer causing more cancer deaths than chronic myelogenous leukemia in the US each year. Its incidence has climbed three-fold over the past 15 years to ~1500 cases per year. No cause for MCC was known until recently and no specific chemotherapy has been found to be effective. Using a genomic screen, we discovered Merkel cell polyomavirus (MCV) as a cause for 80% of MCC. We discovered tumor-specific MCV T antigen mutations are part of MCC tumor evolution, and we and our collaborators developed a highly specific and sensitive MCV VLP capsid ELISA, which was used to examine the natural history of MCV infection, including risk-factors, age-specific prevalence and primary infection. We developed monoclonal antibodies against MCV antigens in tumors. Through knockdown studies, we showed that T antigen expression is essential for MCC tumorigenesis and that MCV large T (LT) increases cellular survivin oncoprotein (BIRC5a). After identifying survivin to be a potential molecular chokepoint for MCC, we tested the Phase II survivin inhibitor, YM155, on both in vitro MCC cell lines and on human MCC xenografts in mice. YM155 is active as a single agent at nanomolar levels in killing or retarding growth of MCC. A multicenter ECOG protocol is now being developed by clinical investigators to examine the efficacy of YM155 among stage III/IV MCC patients based on these preclinical findings. This proposal is a renewal of our R01 to investigate biomarkers in MCV-induced cancers. In this proposal, we seek to leverage our findings to develop and optimize personalized therapy for MCC based on MCV infection: (1) We will first investigate the molecular basis for LT antigen activation of survivin, as well as YM155 inhibition of MCV LT-induced survivin expression. (2) We will optimize YM155 to try to induce durable tumor remission in MCC xenograft models by varying dose, duration of therapy and use of YM155 in combination with other chemotherapeutic agents. (3) We have developed a mouse lentivirus T antigen transduction expression system, which we will use to model mouse MCC development and to measure murine antibody responses to MCV T antigens. (4) We will determine whether patient antibodies to T antigens predict progression or regression of MCV-positive tumors in MCC patients undergoing YM155 treatment. Until recently MCC was both intractable and enigmatic. Our proposal shows that progress in translational science can rapidly proceed after a fundamental discovery: in this case, progress on MCC has advanced from cause to cure research in just over 3 years since MCV was first described. Funding this proposal will allow us to move onto the next generation of experiments to define at a molecular level how MCV causes cancer, how to best monitor MCC progression and how to optimally treat this virus-induced cancer.
Merkel cell carcinoma (MCC) is a severe skin cancer that currently has no specific chemotherapy treatment. We have discovered that most MCC are caused by a virus called Merkel cell polyoma (MCV) and we have found how MCV affects one pathway, called the survivin pathway that contributes to MCC. This proposal will fund studies to identify the precise molecular mechanisms used by MCV to increase survivin in cancer cells and will optimize antiMCC chemotherapies in a model system, which has direct relevance to treatment of MCC. We will also develop new models for MCC that can be used optimizing MCC diagnosis and treatment. Finally, we will determine whether the clinical course of MCC can be predicted with an antibody test against MCV.
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|Shuda, Masahiro; Velásquez, Celestino; Cheng, Erdong et al. (2015) CDK1 substitutes for mTOR kinase to activate mitotic cap-dependent protein translation. Proc Natl Acad Sci U S A 112:5875-82|
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