Building clinically faithful ex vivo indolent lymphoma models for personalized therapy

建立临床忠实的离体惰性淋巴瘤模型以进行个性化治疗

• 批准号: 10470933
• 负责人: Y. Lynn Wang
• 金额: $ 21.42万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-17 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470933
• 关键词: Age; Animal Model; Apoptosis; B-Cell NonHodgkins Lymphoma; BCL2 gene; Behavior; Bone Marrow; Cell Adhesion; Cell Line; Cell Proliferation; Cell Survival; Cell division; Cell model; Cells; Characteristics; Chronic Lymphocytic Leukemia; Clinic; Clinical; Coculture Techniques; Correlation Studies; Data; Development; Disease; Drug Evaluation; Drug Modelings; Fibroblasts; Follicular Lymphoma; Future; Goals; Growth; Histologic; Immune; Individual; Indolent; Interleukin-4; Logistics; Lymphoma; Lymphoma cell; Mantle Cell Lymphoma; Measures; Mission; Modeling; Molecular; Mutation; Nature; Non-Hodgkin' s Lymphoma; Patients; Pharmaceutical Preparations; Physiological; Prior Therapy; Proliferating; Public Health; Refractory; Research; Research Proposals; Resistance; Sampling; Selection for Treatments; System; Testing; Therapeutic; Translational Research; Tumor Tissue; Tumor-Derived; Work; base; bone engineering; cancer type; cell behavior; cell type; clinically relevant; drug development; drug sensitivity; drug testing; expectation; in vivo; in vivo evaluation; individual patient; individualized medicine; inhibitor; innovation; large cell Diffuse non-Hodgkin' s lymphoma; leukemia/lymphoma; lymph nodes; mimicry; neoplastic cell; peripheral blood; personalized medicine; personalized therapeutic; precision drugs; precision medicine; response; targeted treatment; tumor; tumor microenvironment

Project Summary Due to their indolent nature, few cell lines or animal models have been established for chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) compared to other types of cancer. The primary goal of this proposal is to establish an ex vivo indolent lymphoma (iNHL) model that mimics the tumor in vivo microenvironment with faithful readouts of drug sensitivity/ resistance to enable personalized medicine. The central hypothesis is that an ex vivo model with tumor microenvironment (TME) mimicry would make iNHL behave physiologically and provide a clinical faithful model for drug testing. Guided by our preliminary data, the objective will be achieved by the following two specific aims: 1) To refine and build ex vivo iNHL models that will best support tumor cell in vivo behaviors; 2) To validate the models by correlating modeled drug response with patients’ clinical response and/or mutation profiles. In the first aim, optimized ex vivo iNHL models will be created by transducing bone marrow fibroblasts (BMF) with B-cell growth factors, mimicking different cell types found in the tumor milieu in the lymph nodes. Subsequent co-culture-induced changes in cellular behaviors will be measured including cell proliferation and adhesion that are rarely measured in the absence of suitable iNHL models. We then aim to demonstrate that the model is clinically relevant and potentially useful. We will correlate individual modeled cellular response with the clinical response and/or mutation profiles for 60 patients using each patient’s tumor cells to build a personalized therapeutic model. We believe the proposed study is innovative because a practical and clinically faithful personalized Rx model is currently non-existent for indolent lymphoma. It is anticipated that the eventual model will be fast, simple, and economical, enabling a personalized drug trial for individual patients. With the model, we seek to make a stride towards the reality of practicing personalized medicine in the clinic for the benefits of iNHL patients. Successful completion of the proposed research will deliver the following tangible benefits: 1) Models which recapitulate the iNHL-TME that enable evaluation of in vivo behaviors of refractory indolent lymphoma, not currently achievable with the lack of suitable models; 2) Practical (fast, simple, and economical) and clinically faithful models which may be used to guide individualized therapy selection in the clinic leading to direct patient benefits; 3) A large number of genetically heterogeneous tumor models which will streamline the efficiency of future drug development; and 4) A modeling approach potential applicable to other indolent as well as aggressive lymphomas.

项目摘要 由于它们的性质顽强，很少有细胞系或动物模型用于慢性淋巴细胞 与其他类型的癌症相比，白血病（CLL）和卵泡淋巴瘤（FL）。这个主要目标 提案是建立一个模仿体内肿瘤的离体酸性淋巴瘤（INHL）模型 微环境具有忠实的药物敏感性/抵抗力启用个性化药物的读数。 中心假设是具有肿瘤微环境（TME）模拟的离体模型将使INHL 以身体的方式行事，并为药物测试提供临床忠实的模型。在我们的初步数据的指导下 以下两个具体目标将实现目标：1）完善和构建离体模型 这将最能支持体内行为的肿瘤细胞； 2）通过建立建模的关联来验证模型 患者的临床反应和/或突变特征的药物反应。在第一个目的中，优化的离体 INHL模型将通过具有B细胞生长因子的骨髓成纤维细胞（BMF）来创建 模仿淋巴结中肿瘤环境中发现的不同细胞类型。随后的共培养引起的 将测量细胞行为的变化，包括细胞增殖和粘合剂，很少 在没有合适的INHL模型的情况下测量。然后，我们旨在证明该模型在临床上是 相关且可能有用。我们将将单个建模的细胞反应与临床反应相关联 使用每个患者的肿瘤细胞建立个性化疗法的60名患者和/或突变轮廓 模型。我们认为拟议的研究具有创新性，因为一个实用和临床忠实的个性化 RX模型目前不存在惰性淋巴瘤。预计事件模型将是 快速，简单且经济，可以为个别患者进行个性化药物试验。使用模型，我们寻求 迈向诊所中实践个性化医学的现实，以获得INHL的好处 患者。拟议研究的成功完成将带来以下切实的好处：1）模型 这概括了INHL-TME，能够评估难治性顽固性淋巴瘤的体内行为 目前由于缺乏合适的模型而无法实现； 2）实用（快速，简单和经济）和 临床上忠实的模型，可用于指导诊所中的个性化治疗选择，导致 直接患者福利； 3）大量遗传异质肿瘤模型将简化 未来药物开发的效率； 4）一种模拟方法潜在适用于其他唯一的 以及侵略性淋巴瘤。

项目成果

Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication.

• DOI: 10.1038/s41408-021-00429-z
• 发表时间: 2021-02-18
• 期刊: Blood cancer journal
• 影响因子: 12.8
• 作者: Lu P;Wang S;Franzen CA;Venkataraman G;McClure R;Li L;Wu W;Niu N;Sukhanova M;Pei J;Baldwin DA;Nejati R;Wasik MA;Khan N;Tu Y;Gao J;Chen Y;Ma S;Larson RA;Wang YL
• 通讯作者: Wang YL