Pathogenetic and prognostic studies for improved therapy of Merkel cell carcinoma

描述(申请人提供)：默克尔细胞癌(MCC)是一种越来越常见的皮肤癌，与紫外线暴露和免疫抑制有关。与恶性黑色素瘤相比，MCC的致命性是前者的两倍。MCC相关多瘤病毒的里程碑式的发现为在发病机制、预后标志和治疗方面取得实质性进展带来了希望。Nghiem博士是公认的领导者，截至2008年，他是MCC领域以患者为导向的研究人员。这项K24建议将利用广泛和独特的一组临床数据、组织和血液。该计划将为年轻的临床研究人员提供出色的培训机会，使其发展成为以患者为导向的研究人员，并允许Nghiem博士将至少50%的精力集中在以患者为导向的研究和指导上。Nghiem博士是皮肤科研究的联合主任，也是新授予的NIH皮肤科培训补助金的联席主任。为了为以患者为中心的研究实习生提供最佳指导，Nghiem博士与华盛顿大学和弗雷德·哈钦森癌症研究中心的内科、外科和放射肿瘤学家组成的成熟团队密切合作。在Nghiem博士过去十年指导的34名学员中，有33人仍在接受培训，或者已经在五所不同的大学担任教职(12名学员)。华盛顿大学为以患者为导向的研究提供了丰富的潜在受训人员来源，并通过由NIH资助的广泛的转化性健康科学研究所为他们提供资金、课程和指导。已经建立了广泛的协作指导关系，以确保在以患者为导向的研究中对来自不同临床学科的指导对象进行有效的培训。接受指导的人将与患者直接接触，包括同意患者捐献组织/血液，并在稍后联系他们以获得后续数据。他们的培训还将包括遗传、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癌的理解。虽然这些项目侧重于MCC，但培训将广泛适用于人类疾病。三个目标(1-3个)通过美国癌症协会的拨款在2012年前得到资助：目标1.定义在MCC中复发的关键基因异常，Aim 2.开发MCC的共识分期系统，Aim 3.将临床、组织学和分子特征整合到一个诺模图中，以预测MCC的生存。AIMS 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：AIM 4.将病毒状态与MCC的结局联系起来，AIM 5.开发和使用血清学方法来确定MCC患者和对照中MCPyV的流行率，以及AIM 6.定义针对MCC相关多瘤病毒的细胞介导的免疫反应。来自AIMS 4-6的数据将支持在K24奖励期间提交的新NIH R01拨款的申请。

DESCRIPTION (provided by applicant): 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.