Heme oxygenase-1 as a tumor factor and therapeutic target for Kaposi sarcoma

血红素加氧酶-1 作为肿瘤因子和卡波西肉瘤的治疗靶点

• 批准号: 9248335
• 负责人: ASHLEE V. MOSES
• 金额: $ 39.37万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248335
• 关键词: AIDS Malignancy Consortium; Acquired Immunodeficiency Syndrome; Address; Affect; Apoptotic; Attenuated; B-Lymphocytes; Bilirubin; Biological Assay; Biopsy; Cancer Burden; Carbon Monoxide; Cells; Clinical Trials; Country; Data; Developed Countries; Developing Countries; Disease; Endothelial Cells; Environment; Enzymes; Erythrocytes; Etiology; Future; Genetic; Goals; Growth; HIV; Heme; Herpesviridae; Herpesviridae Infections; Highly Active Antiretroviral Therapy; Human; Implant; In Vitro; Incidence; Infection; Integration Host Factors; Intervention; Iron; Kaposi Sarcoma; Knowledge; Laboratories; Life Cycle Stages; Lymphoproliferative Disorders; Lytic Phase; Malignant Neoplasms; Mesoporphyrins; Modeling; Morbidity - disease rate; Multicentric Angiofollicular Lymphoid Hyperplasia; Mus; Neonatal Jaundice; Nodular Neoplasm; Oncogenic; Oncogenic Viruses; Patients; Persons; Pharmacologic Substance; Pharmacology; Phase; Phenotype; Play; Population; Primary Infection; Property; Proteins; Reactive Oxygen Species; Regulation; Research; Role; Running; Skin Kaposi' s Sarcoma; Spindle Cell Sarcomas; Stimulus; Testing; Tissues; Tumorigenicity; Viral; Virus Diseases; Work; base; design; gammaherpesvirus; heme a; heme oxygenase-1; humanized mouse; in vivo; inhibitor/antagonist; innovation; latent infection; malignant phenotype; mortality; mouse model; neoplastic cell; novel therapeutics; novel virus; pathogen; primary effusion lymphoma; public health relevance; therapeutic target; translational study; treatment strategy; tumor; tumorigenesis; tumorigenic; virus host interaction; virus pathogenesis

 DESCRIPTION (provided by applicant): The oncogenic gamma-herpesvirus Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi sarcoma (KS), a tumor of endothelial origin, and two B cell disorders, primary effusion lymphoma and multicentric Castleman's disease. KS is the most common AIDS-associated malignancy and one of the most prevalent cancers overall amongst populations co-infected with HIV and KSHV. Although HAART has greatly reduced KS incidence in developed countries, KS remains a cause of considerable morbidity and mortality worldwide, and effective and inexpensive novel therapies are badly needed. The primary goal of this project is to determine whether heme oxygenase-1 (HO-1), a cellular enzyme that is strongly induced in KSHV-infected endothelial cells (EC) and highly expressed in KS biopsy tissue, is a viable therapeutic target for KS. HO-1 metabolizes heme, a potentially toxic pro-oxidant molecule, to by-products (carbon monoxide, bilirubin, iron) with cytoprotective, proliferative and anti-apoptotic properties. KS spindle cells engulf and degrade heme- containing erythrocytes that extravasate into the tumor, and this distinctive capacity predicts tha KS tumor cells are particularly reliant on HO-1 expression and activity to facilitate degradation o excess heme substrate. We hypothesize that KSHV-induction of HO-1 allows spindle cells to thrive in a high-heme environment, and that pharmacological manipulation of HO-1 should be evaluated for KS therapy. Our preliminary data that support this hypothesis show that HO-1 is required for efficient KSHV infection of EC, that KSHV-infected EC use exogenous heme as a growth stimulus in a HO-1-dependent manner, and that KSHV encodes specific factors that regulate HO-1 expression during different phases of virus infection. Importantly, inhibition of HO-1 activity with stannic mesoporphyrin (SnMP), a HO-1 inhibitor approved for the treatment of neonatal jaundice, attenuated both the pro-viral and pro-growth activity of HO-1. Based on these findings, we propose three complementary yet independent Aims to define the mechanism(s) through which: (i) KSHV induces endothelial HO-1, (ii) HO-1 facilitates KSHV infection of EC, and (iii) KSHV-induced HO-1 promotes tumorigenesis. These Aims integrate genetic and mechanistic EC-based in vitro infection models, and in vivo anti-viral and anti- tumor studies using a recently-established humanized mouse model (Hu-BLT model) for KSHV infection and a tumor-implant model for tumorigenesis. Data will be used to inform the design of a Phase I/II clinical trial run by the AIDS Malignancy Consortium designed to test pharmaceutical grade SnMP in AIDS/KS patients. Overall, this innovative translational study is expected to exert an impact on the KSHV/KS field by identifying and characterizing a novel virus-host interaction, and establishing whether HO-1 is a viable therapeutic target for KS. Knowledge gained should impact the broader fields of anti-tumor therapy and tumor virus pathogenesis.

 描述（由申请人提供）：致癌性γ-疱疹病毒卡波西肉瘤疱疹病毒（KSHV）是卡波西肉瘤（KS）（一种内皮来源的肿瘤）和两种B细胞疾病（原发性渗出性淋巴瘤和多中心卡斯尔曼病）的病原体。 KS 是最常见的与 AIDS 相关的恶性肿瘤，也是同时感染 HIV 和 KSHV 的人群中最常见的癌症之一。尽管HAART大大降低了发达国家KS的发病率，但KS仍然是全世界相当大的发病率和死亡率的一个原因，因此迫切需要有效且廉价的新疗法。该项目的主要目标是确定血红素加氧酶-1 (HO-1)（一种在 KSHV 感染的内皮细胞 (EC) 中强烈诱导并在 KS 活检组织中高度表达的细胞酶）是否是 KS 的可行治疗靶点。 HO-1 将血红素（一种潜在有毒的促氧化剂分子）代谢为具有细胞保护、增殖和抗凋亡特性的副产物（一氧化碳、胆红素、铁）。 KS 梭形细胞吞噬并降解渗入肿瘤的含血红素红细胞，这种独特的能力预示着 KS 肿瘤细胞特别依赖 HO-1 表达和活性来促进过量血红素底物的降解。我们假设 KSHV 诱导的 HO-1 允许梭形细胞在高血红素环境中茁壮成长，并且应该评估 HO-1 的药理学操作以用于 KS 治疗。我们支持这一假设的初步数据表明，HO-1是KSHV有效感染EC所必需的，KSHV感染的EC以HO-1依赖性方式使用外源血红素作为生长刺激物，并且KSHV编码在病毒感染的不同阶段调节HO-1表达的特定因子。重要的是，用锡中卟啉 (SnMP)（一种被批准用于治疗新生儿黄疸的 HO-1 抑制剂）抑制 HO-1 活性，可减弱 HO-1 的促病毒和促生长活性。基于这些发现，我们提出了三个互补但独立的目标来定义以下机制：（i）KSHV诱导内皮HO-1，（ii）HO-1促进KSHV感染EC，以及（iii）KSHV诱导的HO-1促进肿瘤发生。这些目标整合了基于遗传和机制 EC 的体外感染模型，以及使用最近建立的 KSHV 感染人源化小鼠模型（Hu-BLT 模型）和肿瘤发生的肿瘤植入模型进行的体内抗病毒和抗肿瘤研究。数据将用于为 AIDS 恶性肿瘤联盟运行的 I/II 期临床试验的设计提供信息，该试验旨在测试 AIDS/KS 患者的药物级 SnMP。总体而言，这项创新的转化研究预计将通过识别和表征新型病毒-宿主相互作用，并确定 HO-1 是否是 KS 的可行治疗靶点，对 KSHV/KS 领域产生影响。获得的知识应该会影响更广泛的抗肿瘤治疗和肿瘤病毒发病机制领域。