Targeting EZH2 in Germinal Center Derived B-Cell Lymphoma

描述(申请人提供)：大多数B细胞淋巴瘤起源于生发中心(GC)B细胞，包括弥漫性大B细胞淋巴瘤(DLBCL)和滤泡性淋巴瘤(FL)。GCS是对T细胞依赖抗原暴露的反应而形成的暂时性结构，在此期间B细胞经历了增殖和体细胞的超突变。我们发现H3K27组蛋白甲基转移酶EZH2是正常B细胞形成GC所必需的。EZH2通过抑制增殖检查点基因和B细胞退出GC反应所需的基因，在GC B细胞中发挥双重作用。EZH2在DLBCL和FL中广泛表达，但这些肿瘤的一部分获得了EZH2点突变，使该酶能够更有效地三甲基化H3K27。突变体EZH2可诱导更大的启动子H3K27me3和更深层次的沉默EZH2靶标，导致持续的增殖和分化阻断。由于特定小分子抑制剂的开发，EZH2的治疗靶向现在成为可能。这些药物同时抑制DLBCL和FL细胞株的突变和WT EZH2，提示EZH2的依赖可能反映了EZH2的GC谱系作用。然而，对EZH2抑制剂的反应缓慢，可能反映了表观遗传沉默蛋白逆转的动力学。我们假设EZH2靶向治疗对具有特定遗传和表观遗传学特征的DLBCL和FL有效。我们预测，由于它们的缓慢反应动力学，可能会对这些药物产生抗药性。我们假设EZH2抑制剂将与标准和实验性抗淋巴瘤药物协同作用，目标是互补的遗传和表观遗传学定义的途径，但需要进行理论研究才能达到最佳的组合效力。因此，我们的建议将探索DLBCL和FL患者对EZH2依赖的遗传和表观遗传决定因素，将确定对EZH2抑制剂产生获得性耐药性的机制，以及这些药物与其他抗淋巴瘤药物联合使用的最佳方式。最后，我们将在首次对DLBCL患者进行有效的EZH2抑制剂临床试验的背景下进行最先进的相关研究，以验证人类易受EZH2抑制剂影响的淋巴瘤的药效学和肿瘤背景。

DESCRIPTION (provided by applicant): A majority of B-cell lymphomas arise from germinal center (GC) B-cells including diffuse large B-cell lymphomas (DLBCL) and follicular lymphomas (FL). GCs are transient structures that form in response to T- cell dependent antigen exposure within which B-cells undergo proliferation and somatic hypermutation. We find that the H3K27 histone methyltransferase EZH2 is required for normal B-cells to form GCs. EZH2 plays a dual role in GC B-cells by suppressing proliferation checkpoint genes and genes required for B-cells to exit the GC reaction. EZH2 is widely expressed in DLBCL and FL, but a subset of these tumors acquire EZH2 point mutations which enable this enzyme to more efficiently trimethylate H3K27. Mutant EZH2 induces greater promoter H3K27me3 and more profound silencing of EZH2 targets, resulting in sustained proliferation and differentiation blockade. Therapeutic targeting of EZH2 is now possible thanks to the development of specific small molecule inhibitors. These drugs suppress DLBCL and FL cell lines with both mutant and WT EZH2, suggesting that EZH2 dependence may reflect a GC lineage role of EZH2. However, response to EZH2 inhibitors occurs slowly, likely reflecting the kinetics of reversal of epigenetic silencin. We hypothesize that EZH2 targeted therapy will be effective against DLBCL and FL with specific genetic and epigenetic features. We predict that resistance to these agents may occur due to their slow response kinetics. We hypothesize that EZH2 inhibitors will synergize with standard and experimental anti-lymphoma agents targeting complementary genetically and epigenetically defined pathways, but require rationale studies to achieve optimal combinatorial potency. Hence our proposal will explore the genetic and epigenetic determinants linked to EZH2 dependency in DLBCL and FL patients, will identify mechanisms through which acquired resistance might develop to EZH2 inhibitors, and the optimal manner in which these drugs could be combined with other anti-lymphoma drugs. Finally we will perform state of the art correlative studies in the context of the first in man clinical trial of a potent EZH2 inhibitor for DLBCL patients to validate the pharmacodynamics and tumor background of lymphomas susceptible of EZH2 inhibitors in humans.