Pathogenetic and prognostic studies for improved therapy of Merkel cell carcinoma

描述（由申请人提供）：默克尔细胞癌（MCC）是一种与紫外线暴露和免疫抑制相关的日益常见的皮肤癌。与恶性黑色素瘤相比，MCC的致命性是恶性黑色素瘤的两倍。MCC相关多瘤病毒的里程碑式发现为在发病机制、预后标志物和治疗方面取得实质性进展提供了希望。Nghiem博士是一位公认的领导者，截至2008年，他是MCC领域受资助的以患者为导向的研究人员。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，并使Nghiem博士能够将至少50%的精力集中在以患者为导向的研究和指导上。Nghiem博士是皮肤病学研究的联合主任，也是新获得的NIH皮肤病学培训补助金的联合主任。为了提供以患者为导向的研究学员的最佳指导，Nghiem博士与华盛顿大学和弗雷德哈钦森癌症研究中心的医疗、外科和放射肿瘤学家团队密切合作。在Nghiem博士过去十年指导的34名学员中，有33人仍在接受培训或已在五所不同大学担任教职（12名学员）。华盛顿大学为面向患者的研究提供了丰富的潜在学员来源，并通过NIH资助的广泛的转化健康科学研究所促进了他们的资金，课程和指导。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学员进行有效培训。学员将与患者直接接触，包括同意患者捐献组织/血液，并在随后与他们联系以获取随访数据。他们的培训还将涉及遗传学，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）通过美国癌症协会资助到2012年：目标1。定义MCC中复发的关键遗传畸变，目标2。为千年挑战目标目标3制定一个共识分期系统。将临床、组织学和分子特征整合到列线图中以预测MCC的生存。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。MCC中病毒状态和结局的相关性，Aim 5。开发并采用血清学检测方法，以确定MCC患者和对照组中MCPyV的患病率，目标6。定义针对MCC相关多瘤病毒的细胞介导的免疫应答。目标4-6的数据将支持在K24奖励期间提交的新NIH R 01资助申请。

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.