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.

项目概要 套细胞淋巴瘤 (MCL) 是一种罕见但无法治愈的 B 细胞淋巴瘤亚型，总体生存期为 5 年 率约为50%。我中心主导的多中心二期研究为美国的基础 美国食品和药物管理局批准依鲁替尼治疗复发/难治性 MCL。我们的研究揭示了 伊布替尼在复发/难治性 MCL 中具有前所未有的单药活性，总体缓解率为 68%，完全回复率为 21%。然而，在我们的试验中，我们观察到对 约 43% 的入组患者接受依鲁替尼治疗。一旦患者在依鲁替尼治疗后复发，1年 成活率仅为22%；因此，绝大多数 MCL 患者会经历疾病进展 依鲁替尼治疗后 12 个月内死亡，表明标准护理方法失败了 克服依鲁替尼耐药性仍然是一个紧迫的未满足的临床需求。识别普遍突变 潜在的原发性依鲁替尼耐药性，我们对原发性依鲁替尼的临床标本进行了突变分析 依鲁替尼耐药的 MCL 患者以及对该药物表现出持久反应的患者。结果显示 原发性耐药肿瘤而不是表现出持久反应的患者的肿瘤具有 突变主要发生在 BCR/NF-kB 通路基因 (39%)、表观遗传修饰基因 (24%)、PIM1 和 mTOR (18%)，以及 BCL2、MYC、ERBB4 (12%) 等癌基因。大多数突变基因和信号传导 已确定的途径在癌症中通常失调，并且已知在细胞中发挥重要作用 增殖、代谢、存活和恶变；因此，我们推断基因改变 这些途径导致依鲁替尼原发性耐药，而针对这些途径的联合治疗 这些途径可能会克服依鲁替尼的原发性耐药性并提高 MCL 的治疗效果。然而， 这些遗传改变的多样性以及多种途径畸变可能造成的可能性 依鲁替尼耐药性给通过一种或几种治疗克服依鲁替尼耐药性带来了挑战 方案，需要个性化护理。在这个提案中，我们将使用原代肿瘤细胞和 来自对依鲁替尼原发性耐药的 MCL 患者的患者来源的异种移植物，以 1) 识别 通过分子分析确定依鲁替尼耐药的机制，2) 同时确定有效的 克服依鲁替尼体外耐药性的治疗组合，以及 3) 确定能够 成功地靶向体内依鲁替尼耐药性。基因突变将与体外试验相关 治疗结果以确定能够预测个体治疗结果的生物标志物。成功的 拟议研究的完成将确定有效的新型组合疗法来克服依鲁替尼 耐药性，确定依鲁替尼耐药机制并检测能够预测的潜在生物标志物 个体患者的治疗结果，最终建立了一种改变实践的治疗理念 MCL 患者，将通过有效的个性化治疗改善临床结果。

项目成果

Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma.

氧化磷酸化代谢重编程确定了套细胞淋巴瘤的治疗靶点。

• 发表时间: 2019
• 影响因子: 17.1
• 作者: Zhang, Liang;Yao, Yixin;Zhang, Shaojun;Liu, Yang;Guo, Hui;Ahmed, Makhdum;Bell, Taylor;Zhang, Hui;Han, Guangchun;Lorence, Elizabeth;Badillo, Maria;Zhou, Shouhao;Sun, Yuting;Di Francesco, M Emilia;Feng, Ningping;Haun, Randy;Lan, Renny;Macki
• 通讯作者: Macki

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management.

套细胞淋巴瘤：2019 年诊断、发病机制、预测和治疗更新。

• 发表时间: 2019
• 影响因子: 12.8
• 作者: Jain, Preetesh;Wang, Michael
• 通讯作者: Wang, Michael

Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma.

PI3K 信号传导和组蛋白脱乙酰化的双重抑制可阻止套细胞淋巴瘤的增殖并诱导致死。

• 发表时间: 2019
• 影响因子: 8
• 作者: Guo, Hui;Zeng, Dongfeng;Zhang, Hui;Bell, Taylor;Yao, Jun;Liu, Yang;Huang, Shengjian;Li, Carrie J;Lorence, Elizabeth;Zhou, Shouhao;Gong, Tiejun;Jiang, Changying;Ahmed, Makhdum;Yao, Yixin;Nomie, Krystle J;Zhang, Liang;Wang, Michael
• 通讯作者: Wang, Michael

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

370 名套细胞淋巴瘤患者接受依鲁替尼治疗的结果：三项开放标签研究的汇总分析。

• 发表时间: 2017-11
• 影响因子: 6.5
• 作者: Rule, Simon;Dreyling, Martin;Goy, Andre;Hess, Georg;Auer, Rebecca;Kahl, Brad;Cavazos, Nora;Liu, Black;Yang, Shiyi;Clow, Fong;Goldberg, Jenna D;Beaupre, Darrin;Vermeulen, Jessica;Wildgust, Mark;Wang, Michael
• 通讯作者: Wang, Michael

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

B 细胞淋巴瘤患者衍生的异种移植模型使药物发现成为可能，并且是个性化治疗的平台。

• 发表时间: 2017-08-01
• 作者: Zhang, Leo;Nomie, Krystle;Zhang, Hui;Bell, Taylor;Pham, Lan;Kadri, Sabah;Segal, Jeremy;Li, Shaoying;Zhou, Shouhao;Santos, David;Richard, Shawana;Sharma, Shruti;Chen, Wendy;Oriabure, Onyekachukwu;Liu, Yang;Huang, Shengjian;Guo, Hui;Chen, Z
• 通讯作者: Chen, Z