Molecular targets in diffuse large B cell lymphoma

描述（由申请人提供）：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例，每年有近10，000例死亡可归因于该疾病。虽然化疗是治疗的主要手段，但在过去的30年里，用于治疗DLBCL的化疗方案没有改善。在标准化疗中加入利妥昔单抗是治疗该病的一个重大进展。然而，只有大约50%的患有这种疾病的患者在化疗和利妥昔单抗治疗后治愈。在DLBCL患者中进行的60多项临床试验表明没有获益。许多DLBCL临床试验失败的一个重要原因可能是将疾病作为单一实体进行研究，尽管已知其分子异质性。DLBCL患者的基因表达谱表明，肿瘤至少包括两种不同的疾病，具有不同的细胞来源，不同的细胞遗传学差异和对蒽环类化疗方案的不同反应率。在这个建议中，我们展示了DLBCL的分子亚分类如何揭示新的肿瘤易感性，可以在临床上探索。 公共卫生相关性：分子谱分析通过列举差异表达基因和致癌途径为阐明肿瘤生物学提供了新的机会。在弥漫性大B细胞淋巴瘤（最常见的淋巴瘤形式）中，分子谱分析已证明诊断包括至少两个分子亚组，其在基因表达谱以及标准化疗组合方面显著不同。我们提出了一种新的方法，使用弥漫性大B细胞淋巴瘤的分子亚分类，以确定新的治疗目标，最有可能是有效的分子定义的患者群体。

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.