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

描述（由申请人提供）：默克尔细胞癌（MCC）是一种侵袭性人类皮肤癌，在美国每年导致的癌症死亡人数超过慢性髓性白血病。其发病率在过去15年中增加了三倍，达到每年约1500例。直到最近才知道MCC的原因，也没有发现有效的特异性化疗。使用基因组筛选，我们发现默克尔细胞多瘤病毒（MCV）作为80%的MCC的原因。 我们发现肿瘤特异性MCV T抗原突变是MCC肿瘤演变的一部分，我们和我们的合作者开发了一种高度特异性和敏感性的MCV VLP衣壳ELISA，用于检查MCV感染的自然史，包括风险因素，年龄特异性患病率和原发感染。我们开发了针对肿瘤中MCV抗原的单克隆抗体。通过敲低研究，我们发现T抗原表达对于MCC肿瘤发生是必不可少的，并且MCV大T（LT）增加细胞存活素癌蛋白（BIRC 5a）。在确定生存素是MCC的潜在分子阻塞点后，我们在体外MCC细胞系和小鼠中的人MCC异种移植物上测试了II期生存素抑制剂YM 155。YM 155作为单一药剂在纳摩尔水平下在杀死MCC或延缓MCC生长中是有活性的。临床研究人员正在开发一种多中心ECOG方案，以基于这些临床前发现来检查YM 155在III/IV期MCC患者中的疗效。 该提案是我们R 01的更新，以研究MCV诱导的癌症中的生物标志物。在本研究中，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LT抗原激活生存素的分子基础，以及YM 155抑制MCV LT诱导的生存素表达。(2)我们将优化YM 155，以尝试通过改变剂量、治疗持续时间以及YM 155与其他化疗剂的组合使用来在MCC异种移植模型中诱导持久的肿瘤缓解。(3)我们已经开发了一种小鼠慢病毒T抗原转导表达系统，我们将使用它来模拟小鼠MCC的发展和测量小鼠对MCV T抗原的抗体应答。(4)我们将确定患者的T抗原抗体是否能预测接受YM 155治疗的MCC患者中MCV阳性肿瘤的进展或消退。直到最近，MCC还是一个既棘手又神秘的组织。我们的建议表明，转化科学的进展可以在基本发现后迅速进行：在这种情况下，自MCV首次被描述以来，MCC的进展在短短3年内就从病因发展到治愈研究。资助这项提案将使我们能够进入下一代实验，以在分子水平上确定MCV如何导致癌症，如何最好地监测MCC进展以及如何最佳地治疗这种病毒诱导的癌症。

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.