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

MCC 肿瘤特异性生物标志物：默克尔细胞癌合理治疗的基础

• 批准号: 8520225
• 负责人: PATRICK S. MOORE
• 金额: $ 31.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520225
• 关键词: Affect; Age; Antibodies; Antibody Formation; Antigens; Biological Assay; Biological Markers; Biological Models; Bortezomib; Cancer Etiology; Capsid; Cell Line; Cells; Cessation of life; Chronic Myeloid Leukemia; Clinical; Clinical Investigator; Cytostatics; Development; Diagnosis; Disease; Disease Progression; Disease remission; Dose; Doxorubicin; E2F transcription factors; Eastern Cooperative Oncology Group; Enrollment; Enzyme-Linked Immunosorbent Assay; Evolution; Funding; Gene Expression; Genetic Transcription; Genomics; Growth; Human; Immune response; Immunoblotting; Immunoglobulin G; Immunoglobulin M; In Vitro; Incidence; Infection; Investigation; Knock-out; Large T Antigen; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Merkel Cells; Merkel cell carcinoma; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mus; Mutation; Natural History; Nude Mice; Oncogene Proteins; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Polyomavirus; Polyomavirus Infections; Polyomaviruses Large T Proteins; Prevalence; Proteasome Inhibitor; Protein Family; Proteins; Protocols documentation; Randomized; Reporter; Research; Retinoblastoma; Risk Factors; Serum; Skin; Skin Cancer; Small Interfering RNA; Staging; Subfamily lentivirinae; System; Testing; Topoisomerase Inhibitors; Toxic effect; Transgenic Organisms; Translational Research; Treatment Protocols; Viral Proteins; Viral Tumor Antigens; Virus; Virus-like particle; Xenograft Model; Xenograft procedure; arm; base; cancer cell; chemotherapeutic agent; chemotherapy; chromatin immunoprecipitation; cytotoxic; inhibitor/antagonist; killings; mouse model; next generation; pre-clinical; promoter; research study; response; survivin; therapy duration; tumor; tumor xenograft; tumorigenesis

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.

描述（由申请人提供）：默克尔细胞癌（MCC）是一种侵略性的人类皮肤癌，每年比美国慢性粒细胞性白血病多。在过去的15年中，它的发病率已上升了三倍，每年〜1500例。直到最近才知道MCC的原因，并且尚未发现具体的化学疗法有效。使用基因组筛选，我们发现默克尔细胞多瘤病毒（MCV）是MCC 80％的原因。 我们发现肿瘤特异性的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性且敏感的MCV VLP CAPSID 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主要感染。我们在肿瘤中开发了针对MCV抗原的单克隆抗体。通过敲除研究，我们表明T抗原表达对于MCC肿瘤发生至关重要，并且MCV大T（LT）增加了细胞遗传癌蛋白（BIRC5A）。在鉴定出Survivin是MCC的潜在分子障碍之后，我们在体外MCC细胞系和小鼠中的人类MCC异种移植物上都测试了II期Survivin抑制剂YM155。 YM155在杀死或阻滞MCC生长的纳摩尔水平的单个药物中活跃。现在，临床研究人员正在开发一种多中心ECOG方案，以根据这些临床前发现检查III/IV期MCC患者中YM155的功效。 该提案是我们R01的续签，以调查MCV引起的癌症中的生物标志物。在该提案中，我们试图利用基于MCV感染的MCC的个性化疗法来开发和优化个性化疗法：（1）我们将首先研究Survivin的LT抗原激活的分子基础，以及MCV LT诱导的Survivin诱导的Survivin表达的YM155抑制。 （2）我们将通过改变剂量，治疗持续时间和与其他化学治疗剂结合使用的剂量，治疗持续时间和使用YM155的剂量，尝试在MCC异种移植模型中诱导耐用的肿瘤缓解。 （3）我们已经开发了一种小鼠慢病毒T抗原转导系统，我们将用于对小鼠MCC发育进行建模并测量对MCV T抗原的鼠抗体反应。 （4）我们将确定对T抗原的患者抗体是否可以预测接受YM155治疗的MCC患者MCV阳性肿瘤的进展或退化。直到最近，MCC既棘手又神秘。我们的建议表明，转化科学的进步可以在发现基本发现后迅速进行：在这种情况下，自MCV首先描述了MCV以来，MCC的进展已在治愈研究中从事康复研究的进步。为此提案提供资金将使我们能够进入下一代实验，以在分子水平上定义MCV如何导致癌症，如何最好地监测MCC的进展以及如何最佳治疗该病毒诱导的癌症。