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: 8685193
• 负责人: Margaret A Shipp
• 金额: $ 41.38万
• 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/8685193
• 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.

描述(由申请人提供)：我们目前诊断和治疗淋巴系统恶性肿瘤的方法没有反映出关于发病机制和相关合理治疗目标的新数据。例如，两种主要发生在年轻健康成年人的淋巴系统恶性肿瘤，经典型霍奇金淋巴瘤(CHL)和原发性纵隔大B细胞淋巴瘤(MLBCL)，很大程度上是由它们的形态和物理位置来定义的。目前CHL和MLBCL的治疗是基于可用的化疗药物的经验性组合，而不是针对疾病特定的生存途径的靶向方法。结节硬化性霍奇金淋巴瘤(NSHL)和MLBCL是慢性淋巴细胞性白血病最常见的亚型，具有一定的生物学和临床特征。这两种疾病通常表现为局部/纵隔肿瘤，扩散到邻近的而不是远处的结节和器官。原发CHL的一个明显的矛盾特征是存在广泛的、基本上无效的炎性浸润物。原发MLBCL包括分散的浸润性淋巴细胞和不同程度的硬化症；然而，对与宿主相关的抗肿瘤免疫反应知之甚少。我们整合了CHL和MLBCL的全面转录谱和全基因组HD SNP阵列数据，并确定染色体9p24.1扩增以及与PD-1配体及其诱导物JAK2相关的过度表达是这些疾病的主要特征。我们假设：1)疾病特异性的遗传改变和PD-1配体在CHL和MLBCL中的过度表达诱导PD-1信号，PD-1受体+肿瘤浸润性T细胞的耗竭和肿瘤免疫逃逸；2)JAK2进一步诱导PD-1配体的表达，促进肿瘤细胞的增殖。因此，9p24、PD-1配体和JAK2扩增的分子分析可能具有预后意义，PD-1通路和JAK2将成为这些疾病合理的治疗靶点。重要的是，PD-1/PD-1配体轴介导的免疫逃避可以被中和PD-1受体的单抗所抑制，JAK2信号转导可以被临床级小分子所阻断。为此，我们提出了以下具体目标：1.0评估慢性淋巴细胞白血病和MLBCL患者中9p24基因扩增的频率和预后意义；2.0阐明慢性淋巴细胞白血病和MLBCL中PD-L1和PD-L2表达相对差异的基础；3.0评估PD-1配体/PD-1受体阻断在CHL和MLBCL患者中的疗效；以及4.0评估化学JAK2抑制对CHL和MLBCL的影响。拟议的研究将把CHL和MLBCL的全面基因组分析转化为强大的临床相关诊断和预后标志，以及有针对性的、个性化的治疗方法。