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: 8913541
• 负责人: KRISTIE A BLUM
• 金额: $ 31.96万
• 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/8913541
• 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 Trials; Combined Modality Therapy; Cytoplasmic Protein; Data; Development; Disease; Disease remission; Dose; Family; Frequencies; Goals; Health; Hematologic Neoplasms; Homing; Immigration; In Vitro; Lead; 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; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Publishing; Receptor Protein-Tyrosine Kinases; 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; Testing; Therapeutic; Translations; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Work; base; bench to bedside; c-Myc Staining Method; cohort; design; improved; in vivo; inhibitor/antagonist; killings; large cell Diffuse non-Hodgkin' s lymphoma; mRNA Export; neoplastic cell; novel therapeutics; outcome forecast; partial response; phase 1 study; phase 2 study; phase I trial; phase II trial; pre-clinical; prevent; 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 PLCγ2 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-κB 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）细胞存活和增殖的中心途径之一。尽管在过去几年中对于这些疾病的治疗取得了重大进展，但目前在干细胞移植之外没有治愈复发性或难治性CLL或NHL的方法，这表明需要新的治疗选择。BCR途径的关键组分是布鲁顿酪氨酸激酶（BTK），其是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。结合并阻断BTK的伊布替尼在CLL、MCL以及由BCR信号传导驱动的DLBCL的子集中显示出非常有希望的结果。然而，尽管与其他疗法相比，在CLL中使用伊鲁替尼的缓解的令人印象深刻的反应和持久性，但MRD阴性状态通常尚未实现。我们最近确定了伊布替尼耐药患者中BTK（C481）或PLCγ2的突变，这些突变可以解释该亚组患者中伊布替尼疗效的缺乏。因此，在CLL中联合新疗法与伊曲替尼以增加MRD阴性缓解的频率，以及在MCL和DLBCL中联合新疗法以改善缓解率/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相关，包括PI 3 K/AKT、BTK和NF-κB，它们与XPO 1输出的肿瘤抑制蛋白融合。我们先前发表的工作表明，XPO 1是CLL的有效治疗靶点，并促进了XPO 1选择性抑制剂selinexor从实验室到临床的转化。我们正在完成一项赛林克斯单药治疗晚期恶性血液病的I期研究，在淋巴瘤、CLL和急性髓性白血病中观察到了抗肿瘤活性。XPO 1已被证明通过作为替代输出者来调节mRNA子集的表达。我们的数据表明，XPO 1输出参与CLL发病机制和进展的mRNA（即Tcl 1和Btk），而赛林克斯阻止它们的输出和翻译。此外，赛林克斯治疗抑制CLL细胞中的B细胞活化、增殖和迁移，并且在体外和体内对伊曲替尼抗性细胞均有效。我们认为，理解mRNA输出介导的调控机制对于成功设计临床上可行的治疗剂以潜在地实现复发性/难治性CLL/SLL的治愈是重要的。具体而言，该提案旨在提高我们对XPO 1在致癌信号传导背景下的作用的理解，该信号传导对于CLL的发病机制和微环境归巢至关重要，并提出了伊曲替尼和selinexor联合治疗的I期试验。我们相信，这项工作将导致一个新的组合，将是有效的CLL和NHL，并可能克服单一药物耐药机制。