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.

项目总结

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