Pathogenetic and prognostic studies for improved therapy of Merkel cell carcinoma

摘要： 默克尔细胞癌(MCC)是一种日益常见的皮肤癌，与紫外线照射和 免疫抑制。与恶性黑色素瘤相比，MCC的致命性是前者的两倍。地标性建筑 MCC相关多瘤病毒的发现为发病机制和预后方面的实质性进展带来了希望 记号笔和治疗。Nghiem医生是公认的领导者，截至2008年，他是一位以患者为导向的资助医生 MCC领域的研究人员。这项K24计划将利用一套广泛而独特的临床 数据、组织和血液。该项目将为年轻的临床医生提供良好的培训机会。 研究人员要发展成为以病人为中心的研究人员，并允许Nghiem博士至少集中50%的精力 致力于以病人为中心的研究和指导。Nghiem博士是皮肤科和 一项新授予的NIH皮肤科培训补助金。提供以病人为中心的最佳指导 作为研究实习生，Nghiem博士与一支成熟的内科、外科和放射团队密切合作 华盛顿大学和弗雷德·哈钦森癌症研究中心的肿瘤学家。在Nghiem博士的34名实习生中 在过去十年的指导下，有33人仍参与培训或已担任教职。 (12名实习生)在五所不同的大学。华盛顿大学提供了丰富的潜力来源 受训人员进行以患者为导向的研究，并通过 美国国立卫生研究院资助的广泛的转化性健康科学研究所。广泛的协作辅导 已建立关系，以确保对来自不同临床学科的学员进行有效的培训 以病人为中心的研究。指导对象将与患者有直接接触，包括同意患者 组织/献血，并在以后联系他们以获得后续数据。他们的训练还将包括遗传， 免疫学和生物统计学结果分析需要改善我们对这种致命皮肤的理解 癌症。虽然这些项目侧重于MCC，但培训将广泛适用于人类疾病。三 AIMS(1-3)通过美国癌症协会的拨款在2012年前获得资助：AIMS 1.定义关键基因 在MCC中反复出现的像差，Aim 2。开发MCC的共识分期系统，Aim 3。整合 将临床、组织学和分子特征纳入诺模图，以预测MCC的生存。AIMS 4-6将利用 我们独特的MCC资源用于研究新发现的Merkel细胞多瘤病毒：目的4.相关病毒 在MCC中的状况和结果，目标5。开发和使用血清学检测来确定 MCC患者和对照组中的MCPyV，以及目的6。定义针对MCC的细胞介导的免疫反应 MCC相关多瘤病毒。来自AIMS 4-6的数据将支持申请新的NIH R01拨款 在K24奖励期间提交。

ABSTRACT: Merkel Cell Carcinoma (MCC) is an increasingly common skin cancer associated with ultraviolet exposure and immune suppression. Compared with malignant melanoma, MCC is twice as likely to be lethal. The landmark discovery of an MCC-associated polyomavirus offers hope of substantial progress in pathogenesis, prognostic markers, and treatment. Dr. Nghiem is a recognized leader and as of 2008, a funded patient-oriented researcher in the area of MCC. This K24 proposal will take advantage of an extensive and unique set of clinical data, tissues, and blood. This program will provide outstanding training opportunities for young clinical investigators to develop into patient-oriented researchers and allow Dr. Nghiem to focus a minimum of 50% effort on patient-oriented research and mentoring. Dr.Nghiem is a co-director of research in Dermatology and of a newly awarded NIH Training Grant in Dermatology. To provide optimal mentoring of Patient Oriented Research - trainees, Dr. Nghiem works closely with an established team of medical, surgical, and radiation oncologists at the UW and Fred Hutchinson Cancer Research Center. Of the 34 trainees that Dr. Nghiem has mentored over the past ten years, 33 remain involved in their training or have already taken a faculty position (12 trainees) at five different universities. The University of Washington provides a rich source of potential trainees for patient-oriented research and facilitates their funding, coursework and mentoring through an extensive NIH-funded Institute of Translational Health Sciences. Extensive collaborative mentoring relationships have been established to ensure effective training of mentees from various clinical disciplines in patient-oriented research. Mentees will have direct patient contact including consenting patients for tissue/blood donation and contacting them later for follow-up data. Their training will also involve the genetic, immunologic, and biostatistical outcomes analyses needed to improve our understanding of this lethal skin cancer. Although these projects focus on MCC, the training will be broadly applicable to human disease. Three Aims (1-3) are funded through 2012 via an American Cancer Society grant: Aim 1. Define key genetic aberrations that are recurrent in MCC, Aim 2. Develop a consensus staging system for MCC, Aim 3. Integrate clinical, histologic and molecular features into a nomogram to predict survival for MCC. Aims 4-6 will leverage our unique MCC resources to study the newly discovered Merkel cell polyomavirus: Aim 4. Correlate viral status and outcome in MCC, Aim 5. Develop and employ a serologic assay to determine the prevalence of MCPyV in MCC patients and controls, and Aim 6. Define the cell-mediated immune response against the MCC-associated polyomavirus. Data from Aims 4-6 will support an application for a new NIH R01 grant to be submitted during the K24 award period.