Towards The Chemotherapy-Free Treatment of Follicular Lymphoma

描述（由申请人提供）：B细胞受体（BCR）通路是淋巴瘤中一种极好的新治疗靶点（Schatz et al. 2013）。我们的研究解决了以下几点：1）我们希望确切地定义BCR通路是如何在滤泡性淋巴瘤（FL）中激活的。典型途径中的点突变在FL中是罕见的，我们假设基因组畸变（染色体获得/损失）靶向FL中BCR信号传导的关键调节因子。使用功能基因组学方法，我们已经确定EPHA 7作为FL中6 q缺失靶向的BCR调节因子，最近还确定了其他基因。我们的数据揭示了BCR信号传导的新的和已知的调节剂，并提供了潜在的治疗机会（Oricchio et al. 2011）。2)我们已经确定EPHA 7作为BCR调节剂，并开发了一种治疗策略，以恢复EPHA 7的淋巴瘤。我们现在希望进行概念验证研究，以研究这种特定BCR调节剂的治疗潜力。该策略是一种双功能Rituxan/EPHA 7融合抗体，我们的初步数据显示，这种构建体上级单独的Rituxan。需要进一步的工作来定义药理学参数、分布、毒性等。3）BCR信号传导的新的小分子抑制剂显示出很大的前景（例如BTK（依鲁替尼）和PI 3 K δ（例如Idealsib和其他）的抑制剂）。这些药物尚未获得批准，但在滤泡性淋巴瘤中显示出临床活性。然而，反应速度和持久性是有限的。我们推测小分子BCR抑制剂、BCL 2拮抗剂和抗体（Rituxan/EPHA 7）的合理组合将改善结果。我们的初步数据显示了伊鲁替尼和BCL 2抑制剂ABT 199之间的协同作用。我们希望在异种移植物和我们新的小鼠FL模型中测试这些策略。该应用程序的目标是提供强有力的临床前数据，使滤泡性淋巴瘤的临床试验。我们专注于滤泡性淋巴瘤（FL），因为它是惰性B细胞淋巴瘤的最常见形式，目前的治疗（化疗加美罗华）仍然无法治愈。由于缺乏实验模型，与其他淋巴瘤相比，这种疾病在某种程度上被忽视了。我们开发了一种新的FL小鼠模型（Oricchio et al. 2011; Schatz et al. 2011），该模型首次实现了对非转化FL的遗传和治疗研究。我们的应用是一种多管齐下的方法，可以充分利用BCR通路抑制的治疗潜力，并带来新的治疗策略，最大限度地减少细胞毒性暴露。Oricchio，E.，G.南扬古德等人（2011年）。“Eh受体A7是一种可溶性肿瘤 滤泡性淋巴瘤的抑制因子。“细胞147（3）：554-564。Schatz，J.H.，E. Oricchio，et al.（2013）.滤泡性淋巴瘤的治疗“血液学Curr观点。Schatz，J.H.，E. Oricchio，et al.（2011）.“靶向帽依赖性翻译阻断淋巴瘤中AKT和PIM激酶聚集的生存信号。“J Exp Med 208（9）：1799-1807。

DESCRIPTION (provided by applicant): The B-cell receptor (BCR) pathway is an excellent new therapeutic target in lymphoma (Schatz et al. 2013). Our study addresses the following points: 1) We wish to define exactly how the BCR pathway is activated in follicular lymphoma (FL). Point mutations in the canonical pathway are rare in FL and we hypothesize that genomic aberration (chromosomal gains/losses) target key regulators of BCR signaling in FL. Using a functional genomics approach we have already identified EPHA7 as a regulator of BCR that is targeted by 6q deletions in FL, and recently identified additional genes. Our data reveal new and known regulators of BCR signaling and provide potential therapeutic opportunities (Oricchio et al. 2011). 2) We have already identified EPHA7 as a BCR regulator and developed a therapeutic strategy to restore EPHA7 to lymphomas. We now wish to preform proof-of-concept studies to investigate the therapeutic potential of this specific BCR regulator. The strategy is a bi-functional Rituxan/EPHA7 fusion antibody and our preliminary data show that this construct is superior to Rituxan alone. Further work is needed to define pharmacological parameters, distributions, toxicity etc. 3) New small molecule inhibitors of BCR signaling show great promise (e.g. inhibitors of BTK (Ibrutinib) and PI3Kdelta (e.g. Idealsib and others). These drugs are not yet approved but show clinical activity in follicular lymphoma. However, the response rates and durability are limited. We speculate that rational combinations of small molecule BCR inhibitors, BCL2 antagonists and antibodies (Rituxan/EPHA7) will improve outcomes. Our preliminary data show synergy between ibrutinib and the BCL2 inhibitor ABT199. We wish to test these strategies in xenografts and our new murine FL model. The goal of this application is to provide strong preclinical data to enable clinical trials in follicular lymphoma. We focus on Follicular Lymphoma (FL) because it is the most common form of indolent B-cell lymphoma and remains incurable with current therapy (chemotherapy plus Rituxan). The disease has been somewhat neglected compared to other lymphomas owing to a lack of experimental models. We developed a new mouse model of FL (Oricchio et al. 2011; Schatz et al. 2011)and this model for the first time enables genetic and therapeutic studies on non-transformed FLs. Together our application is a multipronged approach to fully exploit the therapeutic potential of BCR pathway inhibition and bring new therapeutic strategies that will minimize cytotoxic exposure. Oricchio, E., G. Nanjangud, et al. (2011). "The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma." Cell 147(3): 554-564. Schatz, J. H., E. Oricchio, et al. (2013). "Progress against follicular lymphoma." Curr Opin Hematol. Schatz, J. H., E. Oricchio, et al. (2011). "Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma." J Exp Med 208(9): 1799-1807.