Towards The Chemotherapy-Free Treatment of Follicular Lymphoma

走向滤泡性淋巴瘤的无化疗治疗

• 批准号: 8670250
• 负责人: Hans-Guido Wendel
• 金额: $ 56.78万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670250
• 关键词: Address; Antibodies; B-Cell Lymphomas; BCL2 gene; Biological; Biological Products; Biology; Cells; Chromosomal Gain; Clinical; Clinical Trials; Combined Modality Therapy; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Disease; Effectiveness; Eph Family Receptors; Experimental Models; Exposure to; Follicular Lymphoma; Genes; Genetic; Genomics; Goals; Health; Indolent; Lead; Learning; Lesion; Lymphoma; Memorial Sloan-Kettering Cancer Center; Modeling; Molecular; Mus; Outcome; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Point Mutation; Pre-Clinical Model; Proto-Oncogene Proteins c-akt; Receptor Activation; Receptor Signaling; Receptors, Antigen, B-Cell; Regimen; Reporting; Research; Roche brand of rituximab; Role; Signal Transduction; Somatic Mutation; Testing; Therapeutic; Therapeutic Studies; Time; Toxic effect; Toxicity due to chemotherapy; Translations; Treatment Failure; Tumor Suppressor Proteins; Work; Xenograft procedure; base; chemotherapy; combinatorial; cytotoxic; functional genomics; improved; inhibitor/antagonist; insight; mouse model; neglect; new therapeutic target; novel therapeutics; pre-clinical; response; small molecule

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.

描述（由申请人提供）：B 细胞受体 (BCR) 途径是淋巴瘤的绝佳新治疗靶点（Schatz 等人，2013）。我们的研究解决了以下几点：1) 我们希望准确定义 BCR 通路在滤泡性淋巴瘤 (FL) 中如何被激活。经典途径中的点突变在 FL 中很少见，我们假设基因组畸变（染色体增益/丢失）针对 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 EPHA7 是 BCR 的调节因子，是 FL 中 6q 缺失的目标，并且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因子，并提供了潜在的治疗机会（Oricchio 等人，2011）。 2）我们已经确定EPHA7作为BCR调节剂，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，以研究这种特定 BCR 调节剂的治疗潜力。该策略是双功能 Rituxan/EPHA7 融合抗体，我们的初步数据表明该构建体优于单独的 Rituxan。需要进一步的工作来定义药理学参数、分布、毒性等。 3）新的 BCR 信号小分子抑制剂显示出巨大的前景（例如 BTK 抑制剂（Ibrutinib）和 PI3Kdelta（例如 Idealsib 等）。这些药物尚未批准，但在滤泡性淋巴瘤中显示出临床活性。然而，反应率和持久性有限。我们推测合理的 小分子 BCR 抑制剂、BCL2 拮抗剂和抗体 (Rituxan/EPHA7) 的组合将改善结果。我们的初步数据显示依鲁替尼和 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大的临床前数据，以便能够进行临床试验 滤泡性淋巴瘤。我们重点关注滤泡性淋巴瘤 (FL)，因为它是惰性 B 细胞淋巴瘤最常见的形式，并且目前的治疗方法（化疗加 Rituxan）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 等人，2011 年；Schatz 等人，2011 年），该模型用于 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，旨在充分利用 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. Nanjangud，等人。 （2011）。 “Eph 受体 A7 是一种可溶性肿瘤 滤泡性淋巴瘤的抑制因子。” Cell 147(3): 554-564. Schatz, J. H., E. Oricchio, et al. (2013)。“对抗滤泡性淋巴瘤的进展。” Curr Opin Hematol. Schatz, J. H., E. Oricchio, et al. (2011)。 AKT 和 PIM 激酶 淋巴瘤。”J Exp Med 208(9): 1799-1807。