Molecular targets in diffuse large B cell lymphoma

描述(申请人提供)：弥漫性大B细胞淋巴瘤(DLBCL)是最常见的非霍奇金淋巴瘤，在美国每年的发病率为25,000，每年有近10,000人死于这种疾病。虽然化疗是治疗DLBCL的主要手段，但在过去的30年里，用于治疗DLBCL的化疗方案并没有得到改善。在标准化疗的基础上加用利妥昔单抗，是该病治疗方面的重大进步。然而，只有大约50%的这种疾病的患者在接受化疗和利妥昔单抗治疗后被治愈。已经有60多项针对DLBCL患者的临床试验显示没有任何益处。DLBCL许多临床试验失败的一个重要原因可能是将这种疾病作为一个单一实体来处理，尽管它是已知的分子异质性。DLBCL患者的基因表达谱显示，肿瘤至少包括两种不同的疾病，起源细胞不同，细胞遗传学差异明显，对以蒽环类药物为基础的化疗方案的应答率不同。在这项建议中，我们展示了DLBCL的分子分类如何揭示了可以在临床上探索的新的肿瘤易感性。公共卫生相关性：通过列举差异表达的基因和致癌途径，分子图谱为解开肿瘤生物学提供了新的机会。在最常见的淋巴瘤形式弥漫性大B细胞淋巴瘤中，分子图谱已经证明，诊断至少由两个分子亚群组成，它们的基因表达谱以及标准的化疗组合都有很大不同。我们提出了一种新的方法，使用弥漫性大B细胞淋巴瘤的分子分类来确定在分子定义的患者组中最有可能有效的新的治疗靶点。

DESCRIPTION (provided by applicant): Diffuse large B cell lymphoma (DLBCL) is the most common form of non Hodgkin lymphoma, with an annual incidence of 25,000 in the United States and nearly 10,000 deaths per year attributable to the disease. Although chemotherapy is the mainstay of therapy, there has been no improvement in the chemotherapy regimens used to treat DLBCL in the past 30 years. The addition of rituximab to standard chemotherapy has been a significant advance in the treatment of the disease. However, only about 50% of patients with this disease are cured after treatment with chemotherapy and rituximab. There have been over 60 clinical trials in patients with DLBCL that have demonstrated no benefit. An important reason for the failure of many clinical trials in DLBCL may be the approach to the disease as a single entity, even though it is known to be molecularly heterogeneous. Gene expression profiling of patients with DLBCL demonstrated that the tumors comprised at least two distinct diseases with different cells of origin, distinct cytogenetic differences and different response rates to anthracycline-based chemotherapy regimens. In this proposal, we demonstrate how the molecular subclassification of DLBCL reveals new tumor-susceptibilities that can be explored in the clinic. PUBLIC HEALTH RELEVANCE: Molecular profiling has provided new opportunities for unraveling tumor biology by the enumeration of differentially expressed genes and oncogenic pathways. In diffuse large B cell lymphoma, the most common form of lymphoma, molecular profiling has demonstrated that the diagnosis comprised at least two molecular subgroups that are dramatically different with regard to their gene expression profile as well as to standard combinations of chemotherapy. We propose a novel approach using the molecular subclassification of diffuse large B cell lymphoma to identify new therapeutic targets that are most likely to be effective in the molecularly defined groups of patients.