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.

项目概要 由于其惰性性质，很少有细胞系或动物模型能够用于慢性淋巴细胞性白血病 与其他类型的癌症相比，白血病（CLL）和滤泡性淋巴瘤（FL）。本次活动的首要目标 建议建立一个模拟体内肿瘤的离体惰性淋巴瘤（iNHL）模型 具有忠实读出药物敏感性/耐药性的微环境，以实现个性化医疗。这 中心假设是具有肿瘤微环境（TME）模拟的离体模型将使 iNHL 表现出生理学特征，并为药物测试提供临床忠实模型。根据我们的初步数据， 该目标将通过以下两个具体目标来实现：1）完善和建立离体iNHL模型 这将最好地支持肿瘤细胞的体内行为； 2）通过关联模型来验证模型 药物反应与患者的临床反应和/或突变谱。第一个目标是离体优化 iNHL 模型将通过用 B 细胞生长因子转导骨髓成纤维细胞 (BMF) 来创建， 模仿淋巴结肿瘤环境中发现的不同细胞类型。随后的共培养诱导 将测量细胞行为的变化，包括很少见的细胞增殖和粘附 在没有合适的 iNHL 模型的情况下进行测量。然后我们的目标是证明该模型在临床上是有效的 相关且可能有用。我们将把个体模型细胞反应与临床反应联系起来 和/或 60 名患者的突变概况，使用每位患者的肿瘤细胞来构建个性化治疗 模型。我们相信所提出的研究具有创新性，因为它是一项实用且临床可靠的个性化研究 目前对于惰性淋巴瘤尚不存在 Rx 模型。预计最终模型将是 快速、简单且经济，可为个体患者提供个性化药物试验。通过模型，我们寻求 为了 iNHL 的利益，朝着在诊所实践个性化医疗的现实迈进一大步 患者。成功完成拟议的研究将带来以下切实的好处：1）模型 概括了 iNHL-TME，能够评估难治性惰性淋巴瘤的体内行为， 由于缺乏合适的模型，目前无法实现； 2）实用（快速、简单、经济）和 临床忠实的模型可用于指导临床个体化治疗选择 患者直接受益； 3）大量的遗传异质性肿瘤模型将简化 未来药物开发的效率； 4) 一种可能适用于其他惰性的建模方法 以及侵袭性淋巴瘤。

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