Pathogenetic and prognostic studies for improved therapy of Merkel cell carcinoma

摘要： 默克尔细胞癌（MCC）是一种越来越常见的皮肤癌，与紫外线暴露有关， 免疫抑制与恶性黑色素瘤相比，MCC的致命性是恶性黑色素瘤的两倍。地标 MCC相关多瘤病毒的发现，为在发病机制、预后 标记物和治疗。Nghiem博士是一位公认的领导者，截至2008年，他是一位受资助的以病人为导向的 MCC领域的研究人员。该K24提案将利用广泛而独特的临床 数据组织和血液该计划将为年轻的临床医生提供出色的培训机会。 研究人员发展成为以患者为导向的研究人员，并允许Nghiem博士专注于至少50% 努力开展以病人为导向的研究和指导。Nghiem博士是皮肤科研究的联合主任， 国家卫生研究院皮肤病学培训基金的一部分为患者提供最佳指导 Nghiem博士与一个医疗、外科和放射治疗的成熟团队密切合作， 华盛顿大学和弗雷德哈钦森癌症研究中心的肿瘤学家。在阮博士的34名受训人员中 在过去十年的指导下，33人仍然参与培训或已经担任教职 (12在五所不同的大学学习。华盛顿大学提供了丰富的潜力来源 培训人员进行面向患者的研究，并通过 NIH资助的转化健康科学研究所。广泛的协作指导 已建立关系，以确保有效培训来自不同临床学科的学员， 以病人为中心的研究。受指导者将与患者直接接触，包括知情同意的患者， 组织/血液捐赠，并联系他们以后的后续数据。他们的训练也将涉及遗传， 免疫学和生物统计学结果分析，以提高我们对这种致命皮肤的理解 癌虽然这些项目侧重于MCC，但培训将广泛适用于人类疾病。三 目标（1-3）通过美国癌症协会资助资助到2012年：目标1。定义关键基因 在MCC中复发的畸变，Aim 2。为千年挑战目标目标3制定一个共识分期系统。整合 将临床、组织学和分子特征整合到列线图中以预测MCC的存活。目标4-6将利用 我们独特的MCC资源来研究新发现的默克尔细胞多瘤病毒：目标4。相关病毒 千年挑战委员会，目标5。开发并使用血清学检测方法，以确定 MCC患者和对照中的MCPyV，以及Aim 6。定义细胞介导的免疫应答， MCC相关多瘤病毒。目标4-6的数据将支持新的NIH R 01资助申请 在K24获奖期间提交。

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.