B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy.
B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy.
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DOI：
10.1158/1078-0432.ccr-16-2703
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发表时间：
2017-08-01
期刊：
影响因子：
--
通讯作者：
Wang M
中科院分区：
文献类型：
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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
B细胞淋巴瘤的患者经常在前线治疗后复发，并且需要新的疗法来提供长期缓解。
我们从16例患有大型B细胞淋巴瘤，地幔细胞淋巴瘤，卵泡淋巴瘤，边缘区淋巴瘤或Burkitt的淋巴瘤中建立了PDX模型，通过将患者肿瘤细胞接种到植入了PDX的人体疾病和现象分析中，通过将患者肿瘤细胞接种。 INIB，口服共价抑制剂研究了布鲁顿的酪氨酸激酶，以阐明依鲁鲁替尼耐药性的机制，并鉴定药物治疗以克服抗药性。
PDX保持了相同的生物学，组织病理学和免疫物理特征，在获得的遗传性肿瘤中，与原始患者肿瘤产生了可比的药物反应。 Elalisib与Ibrutinib结合明显地抑制了依伯替尼的耐药性肿瘤的生长，我们使用了源自临床上ibrutinib的患者的PDX模型来评估各种治疗选择，最终消除了患者外周血液中的肿瘤细胞。
我们的结果表明，B细胞淋巴瘤PDX模型是一种有效的系统，可以预测和个性化疗法并解决B细胞淋巴瘤患者的治疗性耐药性。
Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma PDX (patient-derived xenograft) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options. We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt’s lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice. We subjected the PDX models to histopathological and phenotypical examination, sequencing, and drug efficacy analysis. Primary and acquired resistance to ibrutinib, an oral covalent inhibitor of Bruton’s tyrosine kinase, were investigated to elucidate the mechanisms underlying ibrutinib resistance and to identify drug treatments to overcome resistance. The PDXs maintained the same biological, histopathological, and immunophenotypical features, retained similar genetic mutations and produced comparable drug responses with the original patient tumors. In the acquired ibrutinib-resistant PDXs, PLC-γ2, p65, and Src were down-regulated; however, a PI3K signaling pathway member was up-regulated. Inactivation of the PI3K pathway with the inhibitor idelalisib in combination with ibrutinib significantly inhibited the growth of the ibrutinib-resistant tumors. Furthermore, we used a PDX model derived from a clinically ibrutinib-relapsed patient to evaluate various therapeutic choices, ultimately eliminating the tumor cells in the patient’s peripheral blood. Our results demonstrate that the B-cell lymphoma PDX model is an effective system to predict and personalize therapies and address therapeutic resistance in B-cell lymphoma patients.