Dual targeting of XPO1 and BTK in B cell malignancies

描述(申请人提供)：B细胞受体(BCR)信号通路是参与慢性淋巴细胞白血病(CLL)、外套细胞淋巴瘤(MCL)和弥漫性大B细胞淋巴瘤(DLBCL)细胞生存和增殖的中心通路之一。尽管过去几年在这些疾病的治疗方面取得了重大进展，但目前还没有治疗干细胞移植以外的复发或难治性CLL或NHL的方法，这表明需要新的治疗方案。BCR途径的一个关键组成部分是Bruton酪氨酸激酶(BTK)，它是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。结合和阻断BTK的ibrutinib在CLL、MCL以及由BCR信号驱动的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，伊布鲁替尼在慢性淋巴细胞白血病中的缓解效果和持久性令人印象深刻，但通常还没有达到MRD阴性状态。我们最近在伊布鲁替尼耐药患者中发现了BTK(C481)或PLCγ2突变，这可以解释这类患者缺乏伊布鲁替尼疗效的原因。因此，将新疗法与伊布鲁替尼联合应用于CLL以增加MRD阴性缓解的频率，以及在MCL和DLBCL中联合应用以提高缓解率/缓解时间，是一个主要的治疗目标。这些恶性肿瘤还与几个生存通路的异常激活有关，包括PI3K/AKT、BTK和NF-κB，它们与XPO1输出的肿瘤抑制蛋白合并。我们以前发表的工作表明，XPO1是CLL有效的治疗靶点，并促进了XPO1的选择性抑制剂Selinexor从BASE到临床的翻译。我们正在完成Selinexor在晚期血液系统恶性肿瘤中的单剂I期研究，该研究已在淋巴瘤、CLL和急性髓系白血病中观察到抗肿瘤活性。XPO1已被证明通过作为一种替代的输出子来调节mRNAs的子集的表达。我们的数据表明，XPO1输出参与CLL发病和进展的mRNAs(即TCL1和BTK)，Selinexor阻止它们的输出和翻译。此外，Selinexor治疗抑制CLL细胞中B细胞的激活、增殖和迁移，并在体外和体内对伊布鲁替尼耐药细胞有效。接下来，我们认为，了解信使核糖核酸输出介导的调节机制对于成功设计临床可行的治疗方法具有重要意义，从而有可能治愈复发/难治性CLL/SLL。具体地说，这项建议旨在提高我们对XPO1在致癌信号中的作用的理解，该信号对CLL的发病机制和微环境归巢非常重要，并建议进行伊布鲁替尼和Selinexor联合治疗的I期试验。我们相信，这项工作将导致一种新的组合，将在CLL和NHL中有效，并可能克服单一药物耐药机制。

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.