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

项目总结 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，总生存期为5年 利率约为50%。我们中心领导的一项多中心II期研究是美国 美国食品和药物管理局批准伊布鲁替尼治疗复发/难治性MCL。我们的研究揭示了 伊布鲁替尼在复发/难治性MCL中史无前例的单药活性，总有效率为 68%，完全应答率21%。然而，在我们的试验中，我们观察到对 伊布鲁替尼在大约43%的入选患者中应用。一旦患者在伊布鲁替尼治疗后复发，1年 存活率只有22%；因此，绝大多数经历疾病进展的MCL患者 在伊布鲁替尼治疗在12个月内死亡后，证明标准护理方法正在失败， 克服伊布鲁替尼耐药性仍然是一项迫切的临床需求，尚未得到满足。识别普遍存在的突变 在原发性伊布鲁替尼耐药的基础上，我们对原发性肺癌的临床标本进行了突变分析 对伊布鲁替尼耐药的MCL患者和对该药物表现出持久反应的患者。结果显示， 原发耐药肿瘤而不是出现持久反应的患者的肿瘤具有 突变主要发生在bcr/nf-kB途径基因(39%)、表观遗传修饰基因(24%)、PIM1和 MTOR(18%)，bcl2、myc、ERBB4等癌基因(12%)。大多数突变基因和信号 已确定的通路通常在癌症中被解除调控，并已知在细胞中发挥重要作用 增殖、新陈代谢、生存和恶变；因此，我们推断，基因改变 在这些途径中导致了伊布鲁替尼原发耐药性以及针对这些途径的联合治疗 这些途径可能会克服伊布鲁替尼的原发耐药性，并提高MCL的治疗效果。然而， 这些基因改变的多样性以及多个途径异常可能导致 对伊布鲁替尼的耐药性给用一种或几种治疗方法克服伊布鲁替尼耐药性带来了挑战 养生法，有必要进行个性化护理。在这项提案中，我们将使用原代肿瘤细胞和 对伊布鲁替尼有原发耐药的MCL患者的患者来源的异种移植1)鉴定 通过分子图谱分析伊布鲁替尼耐药的机制，2)同时确定有效 体外克服伊布鲁替尼耐药性的治疗组合，以及3)确定 成功靶向体内对伊布鲁替尼的耐药性。基因突变将与体外培养的 治疗结果，以确定能够预测个别治疗结果的生物标记物。成功 拟议研究的完成将确定有效的新的联合疗法来克服伊布鲁替尼 耐药性，确定伊布鲁替尼的耐药机制，并检测能够预测 个别患者的治疗结果，最终在治疗中建立一种改变实践的概念 这将通过有效的个体化治疗来改善临床结果。

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.