Dual targeting of XPO1 and BTK in B cell malignancies

B 细胞恶性肿瘤中 XPO1 和 BTK 的双重靶向

• 批准号: 9259981
• 负责人: JOHN C. BYRD
• 金额: $ 51.2万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-21 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259981
• 关键词: Acute Myelocytic Leukemia; Agammaglobulinaemia tyrosine kinase; Animal Model; Apoptosis; B lymphoid malignancy; B-Cell Activation; B-Lymphocytes; Binding; Cell Nucleus; Cell Survival; Cells; Chronic; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Combined Modality Therapy; Cytoplasmic Protein; Data; Development; Disease; Disease remission; Dose; Family; Frequencies; Goals; Hematologic Neoplasms; Homing; In Vitro; Location; Lymphoma; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Messenger RNA; Modality; Mutation; Non-Hodgkin' s Lymphoma; Nuclear; Oncogenic; PI3K/AKT; Pathogenesis; Pathway interactions; Patients; Phase; Play; Progression-Free Survivals; Progressive Disease; Protein Export Pathway; Proto-Oncogene Proteins c-akt; Publishing; Receptor Cell; Receptor Signaling; Receptors, Antigen, B-Cell; Refractory; Refractory Disease; Relapse; Reporting; Resistance; Resistance development; Role; SYK gene; Signal Pathway; Signal Transduction; Solid Neoplasm; Stem cell transplant; TEC Protein Tyrosine Kinase; TP53 gene; Testing; Therapeutic; Translations; Tumor Suppressor Proteins; Work; base; bench to bedside; c-myc Genes; cohort; design; improved; in vivo; inhibitor/antagonist; killings; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; mRNA Export; migration; neoplastic cell; new combination therapies; novel therapeutics; outcome forecast; partial response; patient subsets; phase 1 study; phase 2 study; phase I trial; phase II trial; pre-clinical; prevent; public health relevance; resistance mechanism; response; targeted treatment; therapeutic target; therapy resistant; tumor

 DESCRIPTION (provided by applicant): B-Cell Receptor (BCR) signaling is one of the central pathways involved in survival and proliferation of Chronic Lymphocytic Leukemia (CLL), Mantle cell lymphoma (MCL), and Diffuse large B-cell lymphoma (DLBCL) cells. Despite the major progress made over the past years for the treatment of these diseases, no cures are currently available for relapsed or refractory CLL or NHL outside of stem cell transplant indicating the need for novel therapeutic options. A critical component of the BCR pathway is Bruton's tyrosine kinase (BTK), a non- receptor tyrosine kinase in the Tec kinase family, which is expressed predominantly in B-lymphocytes. Ibrutinib, which binds and block BTK, has shown extremely promising results in CLL, MCL, and also a subset of DLBCL driven by BCR signaling. However, despite the impressive responses and durability of remissions with ibrutinib in CLL compared to other therapies, MRD-negative status has generally not been achieved. We have recently defined mutations of either BTK (C481) or PLC¿2 in ibrutinib resistance patients that could explain lack of ibrutinib efficacy in this subset of patients. Therefore the combination of new therapies with ibrutinib in CLL to increase frequency of MRD-negative remissions, and also in MCL and DLBCL to improve response rate/remission duration, represents a major therapeutic goal. These malignancies are also associated with aberrant activation of several survival pathways including PI3K/AKT, BTK, and NF-¿B that merge with tumor suppressor proteins exported by XPO1. Our previous published work has shown that XPO1 is a validated therapeutic target for CLL, and facilitated the translation of selinexor, a selective inhibitors of XPO1, from bench to clinic. We are completing a single agent phase I study of selinexor in advanced hematologic malignancies where anti-tumor activity has been observed in lymphoma, CLL, and acute myeloid leukemia. XPO1 has been shown to regulate expression of a subset of mRNAs by serving as an alternative exporter. Our data indicate that XPO1 exports mRNAs involved in CLL pathogenesis and progression (i.e. Tcl1 and Btk) and that selinexor prevents their export and translation. Additionally, selinexor treatment suppresses B-cell activation, proliferation and migration in CLL cells and is effective both in vitro and in vivo in ibrutinib resistant cells. Moving forth we believe that understanding of mRNA export mediated regulatory mechanisms is important for the successful design of clinically viable therapeutics to potentially achieve a cure for relapse/refractory CLL/SLL. Specifically, this proposal aims to improve our understanding of the role of XPO1 in the context of oncogenic signaling important for the pathogenesis and microenvironment homing of CLL, and proposes a Phase I trial of ibrutinib and selinexor combination therapy. We believe that this work will lead to a new combination that will be effective in CLL and NHL and may overcome single agent resistance mechanisms.

 描述（由申请人提供）：B 细胞受体 (BCR) 信号传导是参与慢性淋巴细胞白血病 (CLL)、套细胞淋巴瘤 (MCL) 和弥漫性大 B 细胞淋巴瘤 (DLBCL) 生存和增殖的中心途径之一尽管过去几年在治疗这些疾病方面取得了重大进展，但目前还没有干细胞以外的治疗复发或难治性 CLL 或 NHL 的方法。移植表明需要新的治疗选择。布鲁顿酪氨酸激酶 (BTK) 是 Tec 激酶家族中的一种非受体酪氨酸激酶，主要在 B 淋巴细胞中表达。 block BTK 已在 CLL、MCL 以及由 BCR 信号驱动的 DLBCL 子集中显示出非常有希望的结果，然而，尽管 ibrutinib 在治疗中取得了令人印象深刻的反应和缓解的持久性。与其他疗法相比，CLL 通常尚未达到 MRD 阴性状态，我们最近定义了 BTK (C481) 或 PLC 的突变。 2 在依鲁替尼耐药患者中，这可以解释依鲁替尼在这部分患者中缺乏疗效的原因，因此，新疗法与依鲁替尼联合治疗 CLL 可以增加 MRD 阴性缓解的频率，并且在 MCL 和 DLBCL 中也可以提高缓解率/缓解持续时间。 ，代表了主要的治疗目标。这些恶性肿瘤还与多种生存途径的异常激活有关，包括 PI3K/AKT、BTK 和 NF-¿ B 与 XPO1 输出的肿瘤抑制蛋白合并，表明 XPO1 是 CLL 的有效治疗靶点，并促进 selinexor（一种选择性抑制剂）的翻译。 XPO1，从实验室到临床，我们正在完成 selinexor 在晚期血液恶性肿瘤中的单药 I 期研究，其中在淋巴瘤、CLL 和急性髓系白血病中观察到抗肿瘤活性，已证明 XPO1 可以调节一个子集的表达。我们的数据表明，XPO1 输出参与 CLL 发病机制和进展的 mRNA（即 Tcl1 和 Btk）以及 selinexor。此外，selinexor 治疗可抑制 CLL 细胞中的 B 细胞活化、增殖和迁移，并且在体外和体内对依鲁替尼耐药细胞均有效。展望未来，我们相信了解 mRNA 输出介导的调节机制非常重要。成功设计临床上可行的疗法，有望治愈复发/难治性 CLL/SLL 具体来说，该提案旨在提高我们对 XPO1 在对发病机制至关重要的致癌信号传导中的作用的理解。和 CLL 的微环境归巢，并提出 ibrutinib 和 selinexor 联合疗法的 I 期试验，我们相信这项工作将产生一种新的组合，对 CLL 和 NHL 有效，并可能克服单药耐药机制。