Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment

简介（由申请人提供）：Warren Phipps博士在华盛顿大学（UW）获得传染病奖学金和流行病学硕士学位，目前在华盛顿大学和弗雷德哈钦森癌症研究中心（FHCRC）担任初级教师职位。该提案描述了一个为期5年的培训计划，这将使他成为卡波西肉瘤（KS）和艾滋病毒相关恶性肿瘤领域的独立研究者。拟议的研究试图通过定义人类疱疹病毒-8 （HHV-8）复制与KS治疗结果之间的关系，并评估HHV-8作为KS患者预后生物标志物的潜力，来解决目前KS分期和治疗的局限性。这个项目建立在我在乌干达坎帕拉的乌干达癌症研究所（UCI）研究HHV-8复制和相关的裂解性HHV-8基因表达的研究基础上，该研究在一个大型前瞻性队列中进行，该队列中有KS和没有KS的人。这些研究的初步数据表明，HHV-8在KS患者口咽和血浆中的复制是频繁的，但个体之间的复制率有所不同。对KS病变中特异性HHV-8 mRNA的测量也表明，肿瘤显示出不同数量的裂解基因转录物，并且裂解mRNA的数量可能与不同的KS病变类型有关。基于这些观察结果，我们假设口腔、血液和组织部位HHV-8复制和裂解基因表达的差异导致了KS的异质临床表现和治疗反应的差异。为了验证这一假设，我们建议对200名hiv相关KS患者进行前瞻性研究，这些患者在UCI开始接受标准抗逆转录病毒治疗（ART）和化疗。我们将在长达一年的治疗过程中连续收集唾液、血浆和KS病变样本，我们将使用聚合酶链反应（PCR）定量标本中的HHV-8，包括评估肿瘤中特异性HHV-8基因mRNA的新型PCR检测。然后，我们将测试这些不同解剖部位的HHV-8复制水平是否与临床表现或预测治疗反应有关。本研究将促进我们对复制HHV-8和裂解基因表达在确定的KS疾病中的生物学作用的理解，并可能对KS的治疗做出重大贡献。如果我们发现HHV-8复制水平预测治疗反应或复发，HHV-8可能是一个有用的生物标志物，可以改善目前的KS分期。如果我们发现HHV-8复制与疾病表现和反应相关，我们的研究也将为在未来的研究中寻求抑制HHV-8作为KS治疗策略提供生物学依据。在整个K23颁奖典礼上，我将得到我的导师，dr。Corey Casper， Larry Corey和Anna Wald，他们在疱疹病毒病毒学和感染相关癌症方面提供了无与伦比的专业知识。该研究还将得到华盛顿大学分子诊断实验室国际公认的PCR专家的实验室支持，以及华盛顿大学教师和FHCRC艾滋病毒/艾滋病研究与预防统计中心（SCHARP）的生物统计学支持。我们小组与UCI研究人员的合作还建立了完成乌干达拟议研究所需的研究基础设施，包括经验丰富的研究人员、标本库和现场PCR实验室。在调研的同时，我的K23 proposal还包括了一份精心设计的职业发展规划。我计划的活动包括高级生物统计学、癌症流行病学和分子病毒学的教学课程。我还将在PCR方法学和癌症病理学方面追求实际的实验室经验，以帮助我成长为一名转化研究人员。为了参加西雅图和乌干达的课程作业和其他职业发展活动，我将在奖励期间在两个地点之间分配时间，每年往返2-3次。通过这个K23奖提出的培训和研究项目，我将很好地开始我作为一个早期职业独立调查员的下一个阶段。在短期内，我的目标是在乌干达建立一个关于HHV-8和KS的富有成效的研究项目。基于我的K23研究结果，我预计将进行一项HHV-8生物标志物验证研究和一项抗HHV-8治疗药物（如更昔洛韦）在KS治疗中的试验。最终，我希望开发一个研究项目，旨在将对疾病发病机制的病毒学机制的理解与开发KS治疗和预防的新方法相结合，这将建立我作为hiv相关恶性肿瘤领域独立研究者的职业生涯。

DESCRIPTION (provided by applicant): Dr. Warren Phipps completed an Infectious Diseases fellowship and an MPH degree in Epidemiology at the University of Washington (UW), and currently holds a junior faculty position at UW and the Fred Hutchinson Cancer Research Center (FHCRC). This proposal describes a 5-year training program which will allow him to develop a career as an independent investigator in the field of Kaposi sarcoma (KS) and HIV-associated malignancies. The proposed studies attempt to address current limitations in KS staging and treatment by defining the relationship between human herpesvirus-8 (HHV-8) replication and KS treatment outcomes and evaluating the potential of HHV-8 to serve as a prognostic biomarker in persons with KS. This project builds on research I conducted during my fellowship studying HHV-8 replication and related lytic HHV-8 gene expression in a large prospective cohort of persons with and without KS at the Uganda Cancer Institute (UCI) in Kampala, Uganda. Preliminary data from these studies show that HHV-8 replication in the oropharynx and plasma of persons with KS is frequent, but that rates vary among individuals. Measurement of specific HHV-8 mRNA in KS lesions also shows that tumors display varying amounts of lytic gene transcripts, and that the quantity of lytic mRNA may be associated with different KS lesion types. Based on these observations, we hypothesize that differences in HHV-8 replication and lytic gene expression at oral, blood, and tissue sites contribute to the heterogeneous clinical manifestations of KS and variability in treatment response. To test this hypothesis, we propose to prospectively study 200 persons with HIV-associated KS initiating treatment with standard antiretroviral therapy (ART) and chemotherapy at the UCI. We will collect saliva, plasma, and KS lesion samples serially over the course of therapy up to one year, and we will quantify HHV-8 in specimens using polymerase chain reaction (PCR), including novel PCR assays to evaluate specific HHV-8 gene mRNA in tumors. We will then test whether levels of HHV-8 replication in these various anatomic sites are associated with clinical presentation or predict treatment response. This proposed study will advance our understanding of the biologic role of replicating HHV-8 and lytic gene expression in established KS disease and could make significant contributions to KS care. If we find that levels of HHV-8 replication predict treatment response or relapse, HHV-8 may be a useful biomarker and could improve current KS staging. If we find that HHV-8 replication is associated with disease presentation and response, our study would also provide a biologic rationale to pursue inhibition of HHV-8 as a KS treatment strategy in future studies. I will be supported throughout the K23 award by my mentors, Drs. Corey Casper, Larry Corey, and Anna Wald, who provide unparalleled expertise in herpesvirus virology and infection-related cancers. The proposed study will also receive laboratory support from internationally-recognized PCR experts at the UW Molecular Diagnostics Laboratory and biostatistical support from faculty at the UW and the Statistical Center for HIV/AIDS Research & Prevention (SCHARP) at FHCRC. Our group's collaboration with investigators at the UCI has also established the research infrastructure needed to complete the proposed studies in Uganda, including an experienced study staff, a specimen repository, and an on-site PCR lab. Along with the research study, my K23 proposal includes a carefully designed career development plan. My planned activities include didactic coursework in advance biostatistics, cancer epidemiology, and molecular virology. I will also pursue practical laboratory experiences in PCR methodology and cancer pathology to help me grow as a translational researcher. In order to participate in coursework and other career development activities in both Seattle and Uganda, I will split my time between the two sites during the award period, making 2-3 roundtrips annually. Through the proposed training and research program in this K23 award, I will be well-positioned to begin my next phase as an early-career independent investigator. In the near term, my goal is to build a productive research program in HHV-8 and KS in Uganda. Based of the findings of my K23 study, I anticipate conducting an HHV-8 biomarker validation study and a trial of anti-HHV-8 therapeutics, such as ganciclovir, in KS treatment. Ultimately, I hope to develop a research program aimed at integrating an understanding of virologic mechanisms of disease pathogenesis with the development of new approaches to KS treatment and prevention that will establish my career as an independent investigator in the field of HIV-associated malignancies.