Overcoming Primary Ibrutinib Resistance in Mantle Cell Lymphoma Using Patient-Derived Models and Molecular Profiling

使用患者衍生模型和分子分析克服套细胞淋巴瘤的原发性依鲁替尼耐药性

• 批准号: 9307555
• 负责人: Michael Wang
• 金额: $ 17.4万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307555
• 关键词: Adverse effects; Agammaglobulinaemia tyrosine kinase; B-Cell Lymphomas; BCL2 gene; Biological Assay; Biological Markers; Categories; Cell Proliferation; Cessation of life; Clinic; Clinical; Clinical Trials; DNA Sequence Alteration; Data; Development; Disease Progression; Disease remission; Drug Combinations; Enrollment; Epigenetic Process; Evaluable Disease; FRAP1 gene; Gene Mutation; Genes; Genetic Markers; Goals; In Vitro; In complete remission; Individual; Knowledge; Malignant - descriptor; Malignant Neoplasms; Mantle Cell Lymphoma; Metabolism; Modeling; Molecular; Molecular Profiling; Mutate; Mutation; Mutation Analysis; NF-kappa B; Oncogenes; Outcome; PIM1 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Play; Primary Neoplasm; Public Health; Refractory; Relapse; Resistance; Role; Sampling; Signal Pathway; Specimen; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; Treatment Protocols; Treatment outcome; United States Food and Drug Administration; Work; Xenograft Model; Xenograft procedure; anticancer activity; base; design; drug sensitivity; effective therapy; experience; improved; in vitro Assay; in vivo; individual patient; inhibitor/antagonist; international center; kinase inhibitor; mouse model; mutant; neoplastic cell; novel; novel therapeutics; patient stratification; personalized care; personalized medicine; personalized therapeutic; phase 2 study; potential biomarker; pre-clinical; predictive marker; predictive of treatment response; relapse patients; resistance mechanism; response; standard of care; therapy resistant; tumor

PROJECT SUMMARY Mantle cell lymphoma (MCL) is a rare but incurable subtype of B-cell lymphoma with an overall 5-year survival rate of approximately 50%. A multiple-center phase II study led by our center served as the basis for the U.S. Food and Drug Administration approval of ibrutinib to treat relapsed/refractory MCL. Our study revealed the unprecedented single-agent activity of ibrutinib in relapsed/refractory MCL, with an overall response rate of 68% and a complete response rate of 21%. Nevertheless, in our trial, we observed primary resistance to ibrutinib in approximately 43% of enrolled patients. Once patients relapse after ibrutinib treatment, the 1-year survival rate is only 22%; therefore, the vast majority of MCL patients who experience disease progression after ibrutinib treatment die within 12 months, demonstrating that standard-of-care approaches are failing and overcoming ibrutinib resistance remains an urgent unmet clinical need. To identify prevalent mutations underlying primary ibrutinib resistance, we performed mutational analysis on the clinical specimens of primary ibrutinib-resistant MCL patients and those who showed durable responses to this drug. The results showed that primary resistant tumors but not the tumors of the patients who displayed durable responses possess mutations predominantly in BCR/NF-kB pathway genes (39%), epigenetic modifier genes (24%), PIM1 and mTOR (18%), and oncogenes such as BCL2, MYC, ERBB4 (12%). Most of the mutant genes and signaling pathways identified are commonly deregulated in cancers and are known to play important roles in cell proliferation, metabolism, survival and malignant transformation; therefore, we deduce that genetic alterations in these pathways contribute to primary ibrutinib resistance and that combination treatments targeting these pathways will likely overcome primary ibrutinib resistance and enhance MCL treatment efficacies. However, the diversity in these genetic alterations and the possibility that multiple pathway aberrations may contribute to ibrutinib resistance create challenges in overcoming ibrutinib resistance with one or few treatment regimens, necessitating the personalization of care. In this proposal, we will use primary tumor cells and patient-derived xenografts from MCL patients who are primary resistant to ibrutinib to 1) identify the mechanisms that underlie ibrutinib resistance via molecular profiling, 2) simultaneously determine effective treatment combinations to overcome ibrutinib resistance in vitro, and 3) identify treatment combinations that successfully target ibrutinib resistance in vivo. The genetic mutations will be correlated with the in vitro treatment results to identify biomarkers capable of predicting individual treatment outcomes. Successful completion of the proposed study will identify effective novel combinatory treatments to overcome ibrutinib resistance, determine ibrutinib-resistant mechanisms and detect potential biomarkers capable of predicting individual patient treatment outcomes, ultimately establishing a practice-changing concept in the treatment of MCL patients, which will improve clinical outcomes through effective personalized therapy.

项目摘要 套细胞淋巴瘤（MCL）是一种罕见的，但无法治愈的亚型B细胞淋巴瘤的总体5年生存 率约50%。我们中心领导的一项多中心II期研究作为美国 美国食品和药物管理局批准伊鲁替尼治疗复发性/难治性MCL。我们的研究显示， 在复发性/难治性MCL中，伊鲁替尼具有前所未有的单药活性，总体缓解率为 完全缓解率为21%。尽管如此，在我们的试验中，我们观察到对 约43%的入组患者接受了伊曲替尼治疗。一旦患者在伊鲁替尼治疗后复发，1年 生存率仅为22%;因此，绝大多数经历疾病进展的MCL患者 在伊曲替尼治疗后12个月内死亡，表明标准治疗方法失败， 克服伊替尼耐药性仍然是一个迫切的未满足的临床需求。为了确定流行的突变 由于潜在的原发性伊鲁替尼耐药，我们对原发性 伊替尼耐药MCL患者和对该药物显示持久应答的患者。结果表明 原发性耐药肿瘤，而不是表现出持久反应的患者的肿瘤， 突变主要发生在BCR/NF-kB通路基因（39%）、表观遗传修饰基因（24%）、PIM 1和 mTOR（18%）和癌基因如BCL 2、MYC、ERBB 4（12%）。大多数突变基因和信号 所鉴定的途径通常在癌症中失调，并且已知在细胞凋亡中起重要作用。 增殖、代谢、存活和恶性转化;因此，我们推断， 在这些途径中导致原发性伊替尼耐药性， 这些途径可能会克服原发性伊克替尼耐药性并增强MCL治疗功效。然而，在这方面， 这些遗传改变的多样性和多途径畸变可能导致 在用一种或几种治疗方法克服伊鲁替尼耐药性方面产生了挑战 方案，需要个性化的护理。在这项提议中，我们将使用原代肿瘤细胞， 来自对伊鲁替尼原发性耐药的MCL患者的患者源性异种移植物，以1）鉴定 通过分子谱分析确定伊鲁替尼耐药的机制，2）同时确定有效的 治疗组合，以克服体外的伊替尼耐药性，和3）鉴定治疗组合， 成功靶向体内的伊鲁替尼耐药性。基因突变将与体外 治疗结果，以确定能够预测个体治疗结果的生物标志物。成功 完成拟议的研究将确定有效的新的联合治疗，以克服伊鲁替尼 耐药性，确定伊替尼耐药机制，并检测能够预测 个体患者的治疗结果，最终在治疗中建立一个改变实践的概念， MCL患者，这将通过有效的个性化治疗改善临床结果。

项目成果

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies.

• DOI: 10.1111/bjh.14870
• 发表时间: 2017-11
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Rule S;Dreyling M;Goy A;Hess G;Auer R;Kahl B;Cavazos N;Liu B;Yang S;Clow F;Goldberg JD;Beaupre D;Vermeulen J;Wildgust M;Wang M
• 通讯作者: Wang M

B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy.

• DOI: 10.1158/1078-0432.ccr-16-2703
• 发表时间: 2017-08-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Zhang L;Nomie K;Zhang H;Bell T;Pham L;Kadri S;Segal J;Li S;Zhou S;Santos D;Richard S;Sharma S;Chen W;Oriabure O;Liu Y;Huang S;Guo H;Chen Z;Tao W;Li C;Wang J;Fang B;Wang J;Li L;Badillo M;Ahmed M;Thirumurthi S;Huang SY;Shao Y;Lam L;Yi Q;Wang YL;Wang M
• 通讯作者: Wang M