Towards The Chemotherapy-Free Treatment of Follicular Lymphoma

描述（由申请人提供）：b细胞受体（BCR）途径是淋巴瘤治疗的一个极好的新靶点（Schatz et al. 2013）。我们的研究解决了以下几点：1)我们希望准确地定义BCR通路在滤泡性淋巴瘤（FL）中是如何被激活的。典型通路中的点突变在FL中很少见，我们假设基因组畸变（染色体获得/损失）针对FL中BCR信号的关键调节因子。使用功能基因组学方法，我们已经确定EPHA7是FL中6q缺失靶向的BCR调节因子，并且最近发现了其他基因。我们的数据揭示了新的和已知的BCR信号调节因子，并提供了潜在的治疗机会（Oricchio et al. 2011）。2)我们已经确定了EPHA7作为BCR调节因子，并开发了一种治疗策略来恢复EPHA7对淋巴瘤的作用。我们现在希望进行概念验证研究，以调查这种特定BCR调节剂的治疗潜力。该策略是一种双功能的Rituxan/EPHA7融合抗体，我们的初步数据表明，这种结构优于单独Rituxan。3) BCR信号传导的新小分子抑制剂（如BTK （Ibrutinib）和PI3Kdelta（如Idealsib等）的抑制剂）显示出巨大的前景。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，响应率和耐久性是有限的。我们推测合理组合小分子BCR抑制剂、BCL2拮抗剂和抗体（Rituxan/EPHA7）将改善预后。我们的初步数据显示伊鲁替尼和BCL2抑制剂ABT199之间的协同作用。我们希望在异种移植物和我们的新小鼠FL模型中测试这些策略。本应用的目的是为滤泡性淋巴瘤的临床试验提供强有力的临床前数据。我们关注滤泡性淋巴瘤（FL），因为它是最常见的惰性b细胞淋巴瘤，目前的治疗方法（化疗加利妥昔单抗）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。总之，我们的应用是一种多管齐下的方法，以充分利用BCR途径抑制的治疗潜力，并带来新的治疗策略，将最大限度地减少细胞毒性暴露。Oricchio， E.， G. Nanjangud，等（2011）。“eph受体A7是一种可溶性肿瘤

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.