Complementary Signaling Pathways In Hodgkin Lymphoma and Related Malignancies

霍奇金淋巴瘤及相关恶性肿瘤的互补信号通路

• 批准号: 8161801
• 负责人: Margaret A Shipp
• 金额: $ 44.97万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-22 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8161801
• 关键词: 9p24; 9p24.1; Adult; Appearance; Attenuated; B-Cell Lymphomas; Binding; Biological; Blood; Cell Line; Cell Proliferation; Chemicals; Chromosomes; Chromosomes, Human, Pair 1; Clinic; Clinical; Data; Diagnosis; Diagnostic; Disease; Distant; Employee Strikes; Epstein-Barr Virus Infections; Frequencies; Genetic; Genetic Enhancer Element; Genome; Genomics; Hodgkin Disease; Immune; Immune response; Immune system; In Vitro; Inflammatory Infiltrate; JAK2 gene; Lead; Ligands; Location; Lymphocyte; Malignant Neoplasms; Malignant lymphoid neoplasm; Manuscripts; Mediastinal; Mediastinal Neoplasms; Mediating; Medicine; Modeling; Molecular; Molecular Profiling; Monoclonal Antibodies; Mus; Mutation; Organ; Outcome; Pathway interactions; Patients; Publications; Published Comment; Relative (related person); Sclerosis; Series; Signal Pathway; Signal Transduction; T cell response; T-Lymphocyte; Testing; Transcription Factor AP-1; Translating; Tumor Escape; base; chemotherapeutic agent; clinically relevant; exhaustion; in vivo; neoplastic cell; overexpression; prognostic; receptor; response; small molecule; therapeutic target; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Our current approaches to the diagnosis and treatment of lymphoid malignancies do not reflect emerging data regarding pathogenetic mechanisms and associated rational treatment targets. For example, two lymphoid malignancies that primarily strike young healthy adults, classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL), are largely defined by their morphologic appearance and physical location. Current treatments for cHL and MLBCL are based on empiric combinations of available chemotherapeutic agents rather than targeted approaches to disease-specific survival pathways. The most common subtype of cHL, nodular sclerosing Hodgkin lymphoma (NSHL), and MLBCL share certain biological and clinical features. Both diseases commonly present as local/mediastinal tumors that spread to adjacent, rather than distant, nodes and organs. One of the defining paradoxical features of primary cHLs is the presence of an extensive, largely ineffective, inflammatory infiltrate. Primary MLBCLs include scattered infiltrating lymphocytes and variable degrees of sclerosis; however, little is known about an associated host anti-tumor immune response. We have integrated the comprehensive transcriptional profiles and whole-genome HD SNP array data in cHL and MLBCL and identified chromosome 9p24.1 amplification and the associated overexpression of PD-1 ligands and their inducer, JAK2, as major features of these diseases. We hypothesize that: 1) the disease-specific genetic alteration and overexpression of PD-1 ligands in cHL and MLBCL induces PD-1 signaling, "exhaustion" of PD-1 receptor+ tumor-infiltrating T cells and tumor immune escape; and 2) JAK2 further induces PD-1 ligand expression and augments tumor cell proliferation. As a consequence, molecular analyses of 9p24, PD-1 ligand and JAK2 amplification will likely have prognostic significance and the PD-1 pathway and JAK2 will represent rational therapeutic targets in these diseases. Importantly, immune evasion mediated by the PD-1/PD-1 ligand axis can be inhibited with neutralizing PD-1 receptor monoclonal antibodies and JAK2 signaling can be abrogated with clinical grade small molecules. For these reasons, we propose the following specific aims: 1.0 Assess the frequency and prognostic significance of 9p24 amplification and increased PD-1 ligand and JAK2 expression in patients with cHL and MLBCL; 2.0 Elucidate the bases for relative differences in PD-L1 and PD-L2 expression in cHL and MLBCL; 3.0 Evaluate the efficacy of PD-1 ligand/PD-1 receptor blockade in patients with cHL and MLBCL; and 4.0 Assess the consequences of chemical JAK2 inhibition in cHL and MLBCL. The proposed studies will translate the comprehensive genomic analyses of cHL and MLBCL into robust clinically relevant diagnostic and prognostic signatures and a targeted, personalized approach to treatment. PUBLIC HEALTH RELEVANCE: Our current approaches to the diagnosis and treatment of lymphoid malignancies do not reflect emerging data regarding pathogenetic mechanisms and associated rational treatment targets. For example, two lymphoid malignancies that primarily strike young healthy adults, classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL), are largely defined by their morphologic appearance and physical location and treated with empiric combinations of available chemotherapeutic agents rather than targeted approaches to disease-specific survival pathways. The proposed studies will translate the comprehensive genomic analyses of cHL and MLBCL into robust clinically relevant diagnostic and prognostic signatures and a targeted personalized approach to treatment.

描述（由申请人提供）：我们目前的诊断和治疗淋巴恶性肿瘤的方法不能反映有关致病机制和相关理性治疗靶标的新兴数据。例如，两种主要袭击年轻健康成年人的淋巴恶性肿瘤，经典的霍奇金淋巴瘤（CHL）和原发性纵隔大型B细胞淋巴瘤（MLBCL），主要由它们的形态学外观和物理位置来定义。 CHL和MLBCL的当前治疗方法基于可用的化学治疗剂的经验组合，而不是针对特异性生存途径的靶向方法。 CHL，结节性硬化霍奇金淋巴瘤（NSHL）和MLBCL最常见的亚型具有某些生物学和临床特征。两种疾病通常都表现为局部/纵隔肿瘤，它们扩散到相邻而不是远处的节点和器官。原发性CHL的定义悖论特征之一是存在广泛的，在很大程度上无效的炎症性浸润。原发性MLBCL包括散射的浸润淋巴细胞和可变程度的硬化症。但是，关于相关宿主抗肿瘤免疫反应知之甚少。我们已将CHL和MLBCL中的全基因组HD SNP阵列数据整合在一起，并确定了9P24.1染色体的扩增以及PD-1配体及其诱导剂JAK2的相关过表达，这是这些疾病的主要特征。我们假设：1）CHL和MLBCL中PD-1配体的疾病特异性遗传改变和过表达会诱导PD-1信号传导，PD-1受体+肿瘤浸润T细胞的“精疲力尽”以及肿瘤免疫逃生； 2）JAK2进一步诱导PD-1配体表达并增强肿瘤细胞的增殖。结果，9P24，PD-1配体和JAK2扩增的分子分析可能具有预后意义，PD-1途径和JAK2将代表这些疾病中的理性治疗靶标。重要的是，可以用中和的PD-1受体单克隆抗体抑制PD-1/PD-1配体轴介导的免疫逃避，并且可以用临床级小分子消除JAK2信号传导。由于这些原因，我们提出以下具体目的：1.0评估CHL和MLBCL患者中9p24扩增的频率和预后意义以及PD-1配体和JAK2表达的增加； 2.0阐明了CHL和MLBCL中PD-L1和PD-L2表达相对差异的碱基； 3.0评估PD-1配体/PD-1受体阻滞在CHL和MLBCL患者中的功效； 4.0评估CHL和MLBCL中化学JAK2抑制作用的后果。拟议的研究将把CHL和MLBCL的全面基因组分析转化为临床上相关的诊断和预后特征以及有针对性的个性化治疗方法。 公共卫生相关性：我们目前的诊断和治疗淋巴恶性肿瘤的方法并不能反映有关致病机制和相关理性治疗靶标的新兴数据。例如，两种主要袭击年轻健康成年人的淋巴恶性肿瘤，经典的霍奇金淋巴瘤（CHL）和原发性纵隔大型B细胞淋巴瘤（MLBCL），在很大程度上取决于它们的形态学外观和物理位置，并用可用的化学治疗方法的经济学结合而不是针对性的方法，而不是针对性的方法，而不是针对性的方法，而不是针对性的疾病代名词。拟议的研究将将CHL和MLBCL的全面基因组分析转化为临床上相关的诊断和预后特征以及有针对性的个性化治疗方法。