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: 8312503
• 负责人: Warren Phipps
• 金额: $ 14.33万
• 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/8312503
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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.

描述（由申请人提供）：Warren Phipps 博士在华盛顿大学 (UW) 完成了传染病研究金和流行病学硕士学位，目前在华盛顿大学和 Fred Hutchinson 癌症研究中心 (FHCRC) 担任初级教职。该提案描述了一项为期 5 年的培训计划，该计划将使他能够作为卡波西肉瘤 (KS) 和 HIV 相关恶性肿瘤领域的独立研究者发展职业生涯。 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当前 KS 分期和治疗的局限性。该项目建立在我在乌干达坎帕拉乌干达癌症研究所 (UCI) 的研究金期间进行的研究的基础上，该研究对患有和不患有 KS 的大型前瞻性队列中的 HHV-8 复制和相关的裂解性 HHV-8 基因表达进行了研究。这些研究的初步数据表明，HHV-8 在 KS 患者的口咽和血浆中复制很频繁，但个体之间的复制率有所不同。对 KS 病变中特定 HHV-8 mRNA 的测量还表明，肿瘤表现出不同数量的裂解基因转录本，并且裂解 mRNA 的数量可能与不同的 KS 病变类型相关。基于这些观察结果，我们假设口腔、血液和组织部位的 HHV-8 复制和裂解基因表达的差异导致了 KS 的异质性临床表现和治疗反应的变异性。为了检验这一假设，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，并使用聚合酶链反应 (PCR) 定量标本中的 HHV-8，包括评估特定 HHV-8 基因的新型 PCR 测定肿瘤中的 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相关。这项拟议的研究将增进我们对复制 HHV-8 和裂解基因表达在已确定的 KS 疾病中的生物学作用的理解，并可能为 KS 护理做出重大贡献。如果我们发现 HHV-8 复制水平可以预测治疗反应或复发，那么 HHV-8 可能是一种有用的生物标志物，并且可以改善当前的 KS 分期。如果我们发现 HHV-8 复制与疾病表现和反应相关，我们的研究还将提供生物学原理，以在未来的研究中将抑制 HHV-8 作为 KS 治疗策略。 在整个 K23 奖励期间，我将得到我的导师 Drs. 的支持。 Corey Casper、Larry Corey 和 Anna Wald 在疱疹病毒学和感染相关癌症方面提供了无与伦比的专业知识。拟议的研究还将获得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，以及华盛顿大学和 FHCRC 艾滋病毒/艾滋病研究与预防统计中心 (SCHARP) 教师的生物统计支持。我们小组与 UCI 研究人员的合作还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、样本库和现场 PCR 实验室。 除了研究之外，我的 K23 提案还包括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方面的教学课程。我还将追求 PCR 方法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转化研究员。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，我将在奖励期间将时间分配在两个地点之间，每年进行 2-3 次往返。 通过 K23 奖项中拟议的培训和研究计划，我将处于有利位置，以作为一名早期职业独立调查员开始我的下一阶段。近期，我的目标是在乌干达的 HHV-8 和 KS 中建立一个富有成效的研究项目。根据我的 K23 研究结果，我预计在 KS 治疗中进行 HHV-8 生物标志物验证研究和抗 HHV-8 疗法（例如更昔洛韦）试验。最终，我希望制定一项研究计划，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，这将使我成为 HIV 相关恶性肿瘤领域的独立研究者。