Targeting the Unique Paracaspase MALT1 to Overcome Ibrutinib Resistance in Relapsed/Refractory MCL Patients

靶向独特的副半胱天冬酶 MALT1 克服复发/难治性 MCL 患者对依鲁替尼的耐药性

• 批准号: 10062488
• 负责人: Changying Jiang
• 金额: $ 18.93万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062488
• 关键词: Address; Agammaglobulinaemia tyrosine kinase; B lymphoid malignancy; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Lymphomas; BCL10 gene; BCL2 gene; Binding; Biochemical; Biological; Biological Assay; CRISPR/Cas technology; Cell Line; Cells; Chronic Lymphocytic Leukemia; Cleaved cell; Clinic; Clinical; Complex; Data; Disease Progression; Drug resistance; Enzymes; FRAP1 gene; Generations; Genes; Genetic Engineering; Goals; Hematologic Neoplasms; Histologic; Human; Human Genome; Hyperactivity; In Vitro; In complete remission; Link; Lymphoma cell; MAP Kinase Gene; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Molecular Profiling; Mus; Mutation; NF-kappa B; Non-Hodgkin' s Lymphoma; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Physiological; Play; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Publishing; Receptor Activation; Refractory; Relapse; Reporting; Resistance; Role; Sampling; Scaffolding Protein; Signal Pathway; Signal Transduction; Signaling Protein; Specimen; Therapeutic Agents; Toxic effect; Translational Research; Tyrosine Kinase Inhibitor; alternative treatment; base; drug sensitivity; effective therapy; exome sequencing; experience; improved; in vitro Model; in vivo; inhibitor/antagonist; innovation; insight; large cell Diffuse non-Hodgkin' s lymphoma; mimetics; mouse model; mucosa-associated lymphoid tissue; mutant; next generation sequencing; novel strategies; novel therapeutics; overexpression; patient derived xenograft model; protein function; recruit; response; side effect; standard of care; therapeutic target; therapy resistant; transcriptomics; ubiquitin ligase

SUMMARY Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that is not yet curable. Both as monotherapies and in combination, the Bruton's tyrosine kinase inhibitor ibrutinib and the BH3 mimetic BCL2 inhibitor venetoclax have proven to be effective treatment options for MCL. However, only 21% of patients who received monotherapies ibrutinib or venetoclax and 71% of patients who received the combined therapy achieved a complete response. Furthermore, mono- and dual resistance frequently develops. Therefore, there is an urgent unmet need to overcome resistance to these agents and to study alternative treatment options. Constitutive NF- κB activation is a hallmark of MCL. Indeed, next generation sequencing analysis of 110 MCL patient samples revealed that genes in the NF-κB signaling pathway had the highest mutation rate (29%), indicating the significant contribution of NF-κB signaling to ibrutinib resistance in MCL. Through whole transcriptomic sequencing, we showed that mucosa-associated lymphoid tissue transformation protein (MALT1) is overexpressed and hyperactive in ibrutinib-resistant and ibrutinib-venetoclax dual-resistant MCL cells. MALT1 is a unique paracaspase within the human genome, and it plays a crucial role in NF-κB signaling, suggesting that MALT1 may be a potential therapeutic target to overcome ibrutinib resistance and ibrutinib-venetoclax dual-resistance without significant off-target side effects. Indeed, MI-2, a MALT1 inhibitor, has been shown to selectively target MALT1 in activated B-cell-like diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Our preliminary data show that MI-2 is highly potent in killing ibrutinib-resistant and ibrutinib-venetoclax dual-resistant MCL cells. To address the underlying mechanisms by which MALT1 contributes to therapeutic resistance and how targeting MALT1 can overcome ibrutinib resistance and ibrutinib-venetoclax dual resistance, we aim to 1) determine the efficacy of MI-2 as a single agent or in combination with other agents in MCL cell lines, primary MCL patient samples, and PDX models in vitro; 2) characterize MALT1-mediated mechanisms underlying MCL disease progression and ibrutinib-venetoclax resistance by introducing MALT1 clinical mutants into MCL cells in vitro; and 3) determine the efficacy of targeting MALT1 alone or with other target(s) to overcome ibrutinib-venetoclax resistance in vivo using MCL PDX mouse models. Successful completion of the proposed study will provide strong evidence demonstrating the role of MALT1 in MCL malignancy and therapeutic resistance and how targeting the unique paracaspase MALT1 may overcome ibrutinib resistance and ibrutinib-venetoclax dual resistance, ultimately leading to clinical strategies to treat ibrutinib and/or venetoclax-refractory/relapsed MCL patients.

总结 套细胞淋巴瘤（MCL）是一种侵袭性B细胞恶性肿瘤，目前尚无法治愈。作为单一疗法 以及组合的布鲁顿酪氨酸激酶抑制剂伊替尼和BH 3模拟BCL 2抑制剂维奈托克 已被证明是MCL的有效治疗选择。然而，只有21%的患者接受 单药治疗伊曲替尼或维奈托克，71%接受联合治疗的患者达到了 完整的回答。此外，单耐药和双耐药也经常出现。因此迫切 需要克服对这些药物的耐药性，并研究替代治疗方案。组成型NF- κB活化是MCL的标志。事实上，110个MCL患者样品的下一代测序分析 结果显示，NF-κB信号通路中的基因突变率最高（29%），表明NF-κB信号通路中的基因突变具有显著性差异。 NF-κB信号传导对MCL中伊鲁替尼耐药的贡献。通过整个转录组测序，我们 显示粘膜相关淋巴组织转化蛋白（MALT 1）过表达， 在伊匹替尼耐药和伊匹替尼-维奈托克双重耐药MCL细胞中过度活跃。MALT 1是一种独特的 人类基因组中的副半胱天冬酶，它在NF-κB信号传导中发挥关键作用，表明MALT 1 可能是克服伊替尼耐药和伊替尼-维奈托克双重耐药的潜在治疗靶点 没有明显的脱靶副作用。事实上，MI-2，一种MALT 1抑制剂，已经显示出选择性靶向 MALT 1在活化B细胞样弥漫性大B细胞淋巴瘤和慢性淋巴细胞白血病中的作用我们的初步 数据显示MI-2在杀死伊替尼抗性和伊替尼-维奈托克双重抗性MCL细胞方面是高度有效的。 为了解决MALT 1导致治疗耐药性的潜在机制以及如何靶向 MALT 1可以克服伊鲁替尼耐药和伊鲁替尼-维奈托克双重耐药，我们的目的是1）确定MALT 1的耐药性。 MI-2作为单一药剂或与其它药剂组合在MCL细胞系、原发性MCL患者 样本和PDX体外模型; 2）表征MALT 1介导的MCL疾病的潜在机制 通过在体外将MALT 1临床突变体引入MCL细胞的进展和伊匹替尼-维奈托克耐药性; 和3）确定单独靶向MALT 1或与其它靶点一起靶向MALT 1以克服伊替尼-维奈托克的功效 使用MCL PDX小鼠模型进行体内抗性。成功完成拟议的研究将提供 强有力的证据表明MALT 1在MCL恶性肿瘤和治疗抗性中的作用，以及如何 靶向独特的paracaspase MALT 1可以克服伊鲁替尼耐药性和伊鲁替尼-维奈托克双重 耐药性，最终导致临床策略治疗伊替尼和/或维奈托克难治性/复发性MCL 患者