Towards The Chemotherapy-Free Treatment of Follicular Lymphoma

描述(由申请人提供)：B细胞受体(BCR)途径是淋巴瘤的极好的新治疗靶点(Schatz等人)。2013)。我们的研究涉及以下几点：1)我们希望明确BCR通路在滤泡性淋巴瘤(FL)中是如何被激活的。典型途径中的点突变在FL中很少见，我们假设基因组异常(染色体获得/丢失)针对FL中BCR信号的关键调节因子。利用功能基因组学方法，我们已经确定EPHA7是BCR的调节因子，它是FL中6q缺失的靶标，最近还发现了其他基因。我们的数据揭示了BCR信号的新的和已知的调节器，并提供了潜在的治疗机会(Oricchio等人。2011年)。2)我们已经确定EPHA7是一种bcr调节因子，并开发了一种治疗策略来恢复淋巴瘤的EPHA7。我们现在希望进行概念验证研究，以调查这种特定的BCR调节剂的治疗潜力。该策略是一种双功能Rituxan/EPHA7融合抗体，我们的初步数据表明，这种构建方法优于单独使用Rituxan。需要进一步的工作来确定药理参数、分布、毒性等。3)BCR信号的新的小分子抑制剂显示出巨大的前景(如BTK(伊布鲁替尼)和PI3K Delta(如伊迪西布等)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，响应率和耐用性是有限的。我们推测，小分子bcr抑制剂、bcl2拮抗剂和抗体(Rituxan/EPHA7)的合理组合将改善结果。我们的初步数据显示，ibrutinib和BCL2抑制剂ABT199之间存在协同作用。我们希望在异种移植和我们的新的小鼠FL模型中测试这些策略。这项应用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成为可能。我们将重点放在滤泡性淋巴瘤(FL)上，因为它是最常见的惰性B细胞淋巴瘤，目前的治疗方法(化疗加利妥昔)仍无法治愈。与其他淋巴瘤相比，由于缺乏实验模型，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等人)。2011年；Schatz等人。2011年)，该模型首次实现了对未转化的FLS的遗传和治疗研究。我们的应用是一种多管齐下的方法，以充分开发bcr途径抑制的治疗潜力，并带来新的治疗策略，将细胞毒性暴露降至最低。Oricchio，E.，G.Nanjangud等人。(2011)。Eph受体A7是一种可溶肿瘤。 滤泡性淋巴瘤的抑制者>，<细胞147(3)：554-564>，沙茨，J.H.，E.Oricchio，等人(2013)，<针对滤泡性淋巴瘤的进展>，Curr Opin hematol，Schatz，J.H.，E.Oricchio，等人(2011)<靶向帽依赖的翻译阻止淋巴瘤中AKT和PIM激酶的生存信号汇聚>，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.