MCC Tumor-Specific Biomarkers: Basis for Rational Therapy of Merkel Cell Carcinom

描述(申请人提供)：默克尔细胞癌(MCC)是一种侵袭性的人类皮肤癌，每年在美国导致的癌症死亡人数超过慢性粒细胞白血病。在过去的15年里，它的发病率上升了三倍，达到每年约1500例。直到最近，MCC的病因还不清楚，也没有发现特定的化疗有效。利用基因组筛查，我们发现默克尔细胞多瘤病毒(MCV)是导致80%的MCC的原因。我们发现肿瘤特异的MCV T抗原突变是MCC肿瘤进化的一部分，我们和我们的合作者开发了一种高度特异和敏感的MCV VLP衣壳ELISA，用于检测MCV感染的自然历史，包括危险因素、年龄特异性患病率和原发感染。我们研制了针对肿瘤中MCV抗原的单抗。通过基因敲除研究，我们发现T抗原的表达在MCC的发生中是必不可少的，并且MCV Large T(LT)增加了细胞内的Survivin癌蛋白(BIRC5a)。在确定Survivin是MCC的潜在分子瓶颈后，我们在体外MCC细胞系和小鼠人MCC异种移植瘤上测试了Survivin II期抑制剂YM155。YM155是一种在纳米分子水平上具有杀伤或延缓MCC生长的单一药物。临床研究人员现在正在开发一种多中心ECOG方案，根据这些临床前发现，检查YM155在III/IV期MCC患者中的疗效。这项建议是对我们的R01的更新，以研究MCV诱导的癌症的生物标记物。在这项建议中，我们试图利用我们的发现来开发和优化基于MCV感染的MCC的个性化治疗：(1)我们将首先研究Survivin的LT抗原激活的分子基础，以及YM155抑制MCV LT诱导的Survivin表达的分子基础。(2)我们将通过改变YM155的剂量、治疗时间和与其他化疗药物的联合使用来优化YM155，试图通过改变剂量、疗程和联合使用来诱导MCC移植模型的持久肿瘤缓解。(3)我们建立了一个小鼠慢病毒T抗原转导表达系统，用于模拟小鼠MCC发育和检测小鼠对MCV T抗原的抗体应答。(4)我们将确定在接受YM155治疗的MCC患者中，患者的T抗原抗体是否可以预测MCV阳性肿瘤的进展或消退。直到最近，MCC还是一个既难对付又神秘的公司。我们的建议表明，在一项基本发现之后，翻译科学的进步可以迅速进行：在这种情况下，自MCV首次被描述以来，在短短3年多的时间里，MCC的进展从病因研究到治疗研究。资助这项提案将使我们能够进入下一代实验，在分子水平上定义MCV如何致癌，如何最好地监测MCC进展，以及如何以最佳方式治疗这种病毒诱导的癌症。 公共卫生相关性：默克尔细胞癌(MCC)是一种严重的皮肤癌，目前还没有特殊的化疗方法。我们已经发现大多数MCC是由一种名为默克尔细胞多瘤(MCV)的病毒引起的，我们已经发现MCV是如何影响一条称为Survivin途径的途径，该途径有助于MCC的形成。这项建议将资助研究，以确定MCV用于增加癌细胞中Survivin的确切分子机制，并将在与MCC治疗直接相关的模型系统中优化抗MCC化疗。我们还将开发新的MCC模型，用于优化MCC的诊断和治疗。最后，我们将确定是否可以通过MCV抗体测试来预测MCC的临床病程。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.