Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment

人类疱疹病毒 8 复制和卡波西肉瘤对治疗的反应

• 批准号: 8512671
• 负责人: Warren Phipps
• 金额: $ 14.24万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512671
• 关键词: AIDS clinical trial group; AIDS/HIV problem; Address; Adriamycin PFS; Africa; African; Anatomic Sites; Automobile Driving; Award; Biological Assay; Biological Markers; Biometry; Biopsy; Bleomycin; Blood; Caring; Clinical; Collaborations; Combination Drug Therapy; Communicable Diseases; DNA; Data; Detection; Development; Development Plans; Diagnostic; Disease; Disease Progression; Epidemiology; Faculty; Fellowship; Fred Hutchinson Cancer Research Center; Frequencies; Future; Ganciclovir; Gene Expression; Genes; Goals; HIV; Herpesviridae; Human Herpesvirus 8; In Vitro; In complete remission; Individual; Inflammatory; Institutes; Kaposi Sarcoma; Laboratories; Lead; Lesion; Lesion by Morphology; Link; Lytic; Lytic Phase; Malignant Neoplasms; Measurement; Mentored Patient-Oriented Research Career Development Award; Mentors; Messenger RNA; Methodology; Methods; Molecular; Molecular Virology; Monitor; Oncogenic; Oncogenic Viruses; Oral; Oropharyngeal; Outcome; Pathogenesis; Pathology; Patients; Persons; Phase; Plasma; Polymerase Chain Reaction; Positioning Attribute; Prevention; Prevention Research; Prognostic Marker; Progressive Disease; Proteins; Recurrent disease; Relapse; Research; Research Infrastructure; Research Personnel; Research Training; Resolution; Role; Saliva; Sampling; Site; Specimen; Stable Disease; Staging; Staging System; Testing; Therapeutic; Time; Tissues; Training Programs; Transcript; Treatment outcome; Uganda; Universities; Vincristine; Viral; Virus; Washington; Work; antiretroviral therapy; base; cancer diagnosis; cancer epidemiology; career; career development; chemotherapy; cohort; design; experience; improved; infection related cancer; lytic gene expression; new therapeutic target; novel; novel strategies; partial response; programs; prospective; repository; research study; response; statistical center; treatment response; treatment strategy; tumor; tumor growth; validation studies; viral detection; virology

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.

简介(由申请人提供)：沃伦·菲普斯博士在华盛顿大学(UW)获得传染病奖学金和公共卫生硕士学位，目前在华盛顿大学和弗雷德·哈钦森癌症研究中心(FHCRC)担任初级教职。这份建议描述了一个为期5年的培训计划，该计划将使他能够在卡波西肉瘤(KS)和艾滋病毒相关恶性肿瘤领域发展成为一名独立调查员。拟议的研究试图通过确定人类疱疹病毒-8(HHV-8)复制和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HHV-8基因在乌干达坎帕拉乌干达癌症研究所(UCI)的一大群患有和不患有KS的预期人群中进行的研究的基础上。这些研究的初步数据显示，HHV-8在KS患者的口咽和血浆中复制是频繁的，但比率因个人而异。对KS皮损中特异性HHV-8mRNA的检测也表明，肿瘤显示不同数量的裂解基因转录本，并且裂解基因的数量可能与不同的KS皮损类型有关。基于这些观察，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的不同临床表现和治疗反应的差异性。为了验证这一假设，我们建议对UCI的200名HIV相关KS患者进行前瞻性研究，这些患者开始接受标准的抗逆转录病毒治疗(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，并将使用聚合酶链式反应(PCR)对样本中的HHV-8进行量化，包括新的PCR方法以评估肿瘤中特定的HHV-8基因mRNA。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。这项拟议的研究将促进我们对复制HHV-8和裂解基因表达在已建立的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复制水平可以预测治疗反应或复发，HHV-8可能是一个有用的生物标志物，并可能改善当前的KS分期。如果我们发现HHV-8复制与疾病的表现和反应有关，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基础。在整个K23奖项期间，我的导师科里·卡斯珀博士、拉里·科里博士和安娜·沃尔德博士将为我提供支持，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。这项拟议的研究还将得到威斯康星州大学分子诊断实验室国际公认的聚合酶链式反应专家的实验室支持，以及威斯康星州大学和费城中心艾滋病毒/艾滋病研究与预防统计中心(SCHARP)的教职员工提供的生物统计学支持。我们小组与UCI的调查人员的合作也建立了在乌干达完成拟议研究所需的研究基础设施，包括经验丰富的研究人员、标本储存库和现场PCR实验室。除了这份研究报告，我的K23提案还包括一份精心设计的职业发展计划。我计划的活动包括生物统计学、癌症流行病学和分子病毒学的教学课程。我还将寻求在聚合酶链式反应方法学和癌症病理学方面的实际实验室经验，以帮助我成长为一名翻译研究人员。为了参加西雅图和乌干达的课程和其他职业发展活动，我将在获奖期间在这两个地点之间分配我的时间，每年往返2-3次。通过这个K23奖项中建议的培训和研究计划，我将处于有利地位，开始我的下一个阶段，作为一名职业生涯早期的独立调查员。近期，我的目标是在乌干达建立一个针对HHV-8和KS的富有成效的研究项目。根据我的K23研究结果，我预计将进行一项HHV-8生物标记物验证研究，并在KS治疗中进行抗HHV-8疗法的试验，如更昔洛韦。最终，我希望开发一个研究计划，旨在将对疾病发病机制的病毒学机制的理解与KS治疗和预防的新方法的开发相结合，这将奠定我作为艾滋病毒相关恶性肿瘤领域的独立研究员的职业生涯。