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，是一种与艾滋病相关的恶性肿瘤（AIDS-KS），并且是HIV感染者中最重要的口腔恶性肿瘤。 KS可采用局部治疗、抗逆转录病毒治疗和化疗治疗；然而，估计超过一半的 KS 患者无法治愈。 KS 的特点是由 KSHV 基因引起的梭形细胞增殖和血管生成失调。基于发病机制的靶向治疗 AIDS-KS 的成功有限，例如使用 mTORC1 和 PDGFR 抑制剂，这表明我们迫切需要加深对支持 KS 肿瘤发生的病毒和宿主因素相互作用的了解，以开发靶向治疗；更重要的是，为当前的疗法提供信息。使用我们实验室开发的 Rac1 依赖性和 KSHV 依赖性 KS 肿瘤发生的动物模型，我们在分子上描绘了一个致癌旁分泌轴，将 KSHV 致癌基因 vGCPR 的表达与旁分泌因子的分泌联系起来，以确定新的治疗靶点。以公正的方式进行的新颖研究使我们得出：1) 确定 PDGFR-α (PGFRA) 是 KS 中激活的最有效的致癌驱动信号级联，指出 PDGFRA 作为抗 KS 治疗的靶点 2) 确定 PDGFRA+ 间充质干细胞 (MSC) 是潜在的 KS 致癌祖细胞。我们假设 PDGFRA 的显着激活及其在肿瘤中的驱动作用是 KSHV 内在能力的结果，该能力靶向该途径以增加 PDGFRA+ 靶 MSC 中的感染性、持久性和复制性。 (AIM 1) 将研究 PDGFRA 在 PDGFRA+ MSC KS 祖细胞的 KSHV 感染和肿瘤发生中的作用：(AIM 2) 将确定有利于 PDGFRA 持续激活的宿主病毒相互作用。 （目标 3）将寻求利用遗传和药物抑制研究以及 NGS (RNASeq) 来识别和靶向 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