Interplay Between KSHV and PDGFRA in AIDS-Kaposi's Sarcoma Oncogenesis

KSHV 和 PDGFRA 在艾滋病-卡波西肉瘤肿瘤发生中的相互作用

• 批准号: 9210609
• 负责人: Pascal J. Goldschmidt-Clermont
• 金额: $ 45.72万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210609
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Animal Model; Anti-Retroviral Agents; Biological; Biology; Cancer Etiology; Cells; Characteristics; Clinical Research; Development; Drug Combinations; Gene Targeting; Genes; Genetic; Genetic Transcription; HIV; Herpesviridae; Herpesviridae Infections; Human; Individual; Integration Host Factors; Kaposi Sarcoma; Lead; Lesion; Local Therapy; Lytic; Lytic Phase; Malignant Neoplasms; Mediating; Mesenchymal Stem Cells; Molecular; Mus; Oncogenes; Oncogenic; Oral cavity; PDGFRA gene; PDGFRB gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Platelet-Derived Growth Factor; Principal Investigator; Recruitment Activity; Resistance; Role; Sampling; Signal Transduction; Stem cells; Testing; Therapeutic; Tumor Biology; Viral; Virus; Work; angiogenesis; base; cancer type; chemotherapy; in vivo; inhibitor/antagonist; new therapeutic target; novel; novel strategies; novel therapeutic intervention; paracrine; prevent; progenitor; programs; public health relevance; response; success; targeted treatment; transcriptome; transcriptome sequencing; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Kaposi' s sarcoma (KS), caused by the KS herpesvirus (KSHV) is an AIDS-associated malignancy (AIDS-KS) and is the most important malignancy of the oral cavity in HIV infected individuals. KS can be treated with local therapy, anti-retroviral therapy and chemotherapy; however, it is estimated more than a half of KS patients will not be cured. KS is characterized by the proliferation of spindle cells and deregulated angiogenesis caused by KSHV genes. The limited success of targeted pathogenesis-based therapies in AIDS- KS such as the use of mTORC1 and PDGFR inhibitors indicate the urgent need to increase our understanding of the interplay of viral and host factors underpinning KS oncogenesis for development of targeted therapies; and more importantly, to inform current therapies. Using animal models of Rac1-dependent and of KSHV- dependent KS oncogenesis developed in our lab, we molecularly delineate an oncogenic paracrine axis connecting the expression of the KSHV oncogene vGCPR with secretion of the paracrine factors in order to define novel therapeutic targets. Novel studies carried out in an unbiased manner led us to: 1) Identify PDGFR- alpha (PGFRA) as the most potent oncogenic driver signaling cascade activated in KS pointing to PDGFRA as a target for anti-KS therapies 2) Identify PDGFRA+ mesenchymal stem cells (MSC) as potential KS oncogenic progenitors. We hypothesize that the prominent activation of PDGFRA and its driver role in the tumors is a consequence of the intrinsic ability of KSHV to target this pathway to increase infectivity, persistence and replication in PDGFRA+ target MSC. (AIM 1) Will study the role of PDGFRA in KSHV infection of PDGFRA+ MSC KS progenitors and oncogenesis: (AIM 2) Will Identify host viral interactions conducive to sustained activation of PDGFRA. (Aim 3) Will seek to use genetic and drug inhibition studies and NGS (RNASeq) to identify and targeting mechanisms of PDGFRA-mediated tumorigenesis in KSHV infected tumors. This work will: 1) Identify phenotypic characteristics of the KS progenitor and how the biology of KSHV in these cells leads to oncogenesis 2) Identify key pathogenic mechanisms and new therapeutic approaches 3) Understand the interplay between PDGFRA and KSHV biology in KS tumors and how it affects pathogenesis and response to therapy

 描述（由申请人提供）：卡波西肉瘤（KS）由KS疱疹病毒（KSHV）引起，是一种艾滋病相关恶性肿瘤（AIDS-KS），是HIV感染者口腔中最重要的恶性肿瘤。KS可以通过局部治疗、抗逆转录病毒治疗和化疗来治疗;然而，估计超过一半的KS患者将无法治愈。KS的特征在于由KSHV基因引起的梭形细胞的增殖和失调的血管生成。艾滋病- KS中基于靶向病因的治疗（如使用mTORC 1和PDGFR抑制剂）的有限成功表明，迫切需要增加我们对支持KS肿瘤发生的病毒和宿主因素相互作用的理解，以开发靶向治疗;更重要的是，为当前的治疗提供信息。使用我们实验室开发的Rac 1依赖性和KSHV依赖性KS肿瘤发生的动物模型，我们从分子上描绘了连接KSHV致癌基因vGCPR表达与旁分泌因子分泌的致癌旁分泌轴，以确定新的治疗靶点。以无偏见的方式进行的新研究使我们：1）鉴定PDGFR-α（PGFRA）为KS中激活的最有效的致癌驱动信号级联，指出PDGFRA为抗KS治疗的靶点2）鉴定PDGFRA+间充质干细胞（MSC）为潜在的KS致癌祖细胞。我们假设PDGFRA的显著激活及其在肿瘤中的驱动作用是KSHV靶向该途径以增加PDGFRA+靶MSC中的感染性、持久性和复制的内在能力的结果。(AIM 1）将研究PDGFRA在KSHV感染PDGFRA+ MSC KS祖细胞和肿瘤发生中的作用：（目的2）将鉴定有利于PDGFRA持续激活的宿主病毒相互作用。(Aim 3）将寻求使用遗传和药物抑制研究和NGS（RNASeq）来鉴定和靶向KSHV感染肿瘤中PDGFRA介导的肿瘤发生机制。这项工作将：1）确定KS祖细胞的表型特征以及这些细胞中KSHV的生物学如何导致肿瘤发生2）确定关键的致病机制和新的治疗方法3）了解KS肿瘤中PDGFRA和KSHV生物学之间的相互作用以及它如何影响发病机制和对治疗的反应