Complementary Signaling Pathways In Hodgkin Lymphoma and Related Malignancies

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并未反映有关发病机制和相关合理治疗靶点的新数据。例如，主要侵袭年轻健康成人的两种淋巴恶性肿瘤，经典霍奇金淋巴瘤（cHL）和原发性纵隔大B细胞淋巴瘤（MLBCL），主要由其形态学外观和物理位置定义。目前对cHL和MLBCL的治疗是基于可用化疗药物的经验性组合，而不是针对疾病特异性生存途径的靶向方法。cHL最常见的亚型，结节硬化性霍奇金淋巴瘤（NSHL）和MLBCL共享某些生物学和临床特征。这两种疾病通常表现为局部/纵隔肿瘤，扩散到邻近而不是远处的淋巴结和器官。原发性cHL的一个明确的矛盾特征是存在广泛的、大部分无效的炎性浸润。原发性MLBCL包括分散的浸润淋巴细胞和不同程度的硬化;然而，对相关的宿主抗肿瘤免疫应答知之甚少。我们整合了cHL和MLBCL中的全面转录谱和全基因组HD SNP阵列数据，并将染色体9p24.1扩增和PD-1配体及其诱导物JAK2的相关过表达确定为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诱导PD-1信号传导、PD-1受体+肿瘤浸润性T细胞的"耗竭"和肿瘤免疫逃逸;和2）JAK2进一步诱导PD-1配体表达并增强肿瘤细胞增殖。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途径和JAK2将代表这些疾病的合理治疗靶点。重要的是，由PD-1/PD-1配体轴介导的免疫逃避可以用中和PD-1受体单克隆抗体来抑制，并且JAK 2信号传导可以用临床级小分子来消除。基于这些原因，我们提出了以下具体目标：1.0评估cHL和MLBCL患者中9p24扩增和PD-1配体和JAK2表达增加的频率和预后意义; 2.0阐明cHL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受体阻断剂在cHL和MLBCL患者中的疗效;和拟议的研究将把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特征以及有针对性的个性化治疗方法。

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.