Preclinical Models and Therapeutics Core

临床前模型和治疗核心

• 批准号: 10477225
• 负责人: Giorgio Inghirami
• 金额: $ 15.8万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477225
• 关键词: 3-Dimensional; Animals; Applications Grants; Automobile Driving; Bioinformatics; Biological Assay; Biology; Biometry; Cancer Biology; Cancer Model; Cancer Patient; Cell Line; Clinical; Clinical Research; Collaborations; Complex; Cryopreservation; Cryopreserved Tissue; Data; Data Analyses; Defect; Development; Dissection; Drug Screening; Drug resistance; EGFR gene; End Point Assay; Engineering; Evaluation; Fingerprint; Fostering; Funding; Generations; Genetic; Genomics; Hematological Disease; Hematology; Heterogeneity; Human; Immunocompromised Host; In Vitro; Intervention; Investigational Drugs; Knowledge; Lesion; Libraries; Lymphoma; Malignant Neoplasms; Mature T-Lymphocyte; Mission; Modality; Modeling; Molecular; Molecular Diagnosis; Molecular Profiling; Mus; Neoplasms; Organ; Organoids; Pathologic; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Preclinical Testing; Preparation; Primary Lesion; Procedures; Prognosis; Property; Public Health; Reagent; Reproducibility; Research; Research Personnel; Role; Sampling; Solid; Standardization; Stratification; T-Cell Lymphoma; T-Cell and NK-Cell Neoplasm; Testing; Therapeutic; Tissue Sample; Transgenic Organisms; Treatment Protocols; Tumor-Derived; Validation; Work; Xenograft Model; Xenograft procedure; base; biobank; cancer therapy; cancer type; data mining; data repository; design; efficacy evaluation; established cell line; functional genomics; improved; in vitro Model; in vitro activity; in vivo; individual response; innovation; large cell Diffuse non-Hodgkin' s lymphoma; medical schools; member; mouse model; novel; novel therapeutic intervention; pre-clinical; preclinical evaluation; preclinical trial; predictive modeling; programs; public repository; response; success; targeted treatment; therapeutic target; three dimensional cell culture; tissue resource; transcriptome sequencing; translational cancer research; treatment response; tumor; tumor heterogeneity; tumor xenograft

Contact PD/PI: Rimsza, Lisa Shared-Res-Core-003 (458) The Preclinical Models and Therapeutics Core (PMTC) will generate/assemble and characterize a wide array of patient derived tumor xenograft (PDTX) models and patient derived organoids (PDO). We will use PDTX models to conduct in vivo preclinical animal studies described in Projects 1, 2, 3 and 4. This will allow for efficient and consistent evaluation of the efficacy of the novel therapeutic approaches proposed in each of the Projects. Translational cancer research has been greatly facilitated by the demonstration that human tumors can be grown as xenografts in immunocompromised mice, and the use of PDTX has significantly increased the public knowledge of cancer biology and improved the preclinical evaluation and predictability of investigational drugs. Historically, as high as 85% of drugs with in vitro activity have failed in human studies. More importantly, PDTX were proven to maintain many of the features of the original patient tumors, including expression phenotypes, genomic landscape and tumor heterogeneity and intrinsic properties such as their ability to colonized/disseminate into specific organs. This allows for the design and implementation of highly informative pre-clinical trials, capable of anticipating the responses of individual cancer patients. PDTX serve as a renewable, quality-controlled tissue resource for preclinical evaluation of novel treatment regimens and will be the principal platform for evaluation of the efficacy of the targeted therapies, outlined in the Projects of this current application. Although many PDTX have been established from solid cancers, PDTX from hematological disorders are still rare and no comprehensive libraries exist. Here we will focus on the generation and characterization of PDTX from DLBCL and T-cell lymphoma, which remains an unmet clinical need. It is now recognized that the poor therapeutic success in this arena is largely due to the complex heterogeneity of these neoplasms, as well as, in the case of mature T-cell neoplasms, the lack of “bona fide” cell lines or reproducible and informative mouse models. Both PDTX and derived 2D/3D in vitro models will be molecularly profiled (WES/target sequencing, total RNA-Seq and ERBBS) and validated using functional approaches. Preclinical testing will be available using a battery of conventional and novel compounds. PDTX are particularly useful for in vivo mechanistic studies through the use of PDOs, and the information from these studies will be instrumental in understanding the biology, stratification criteria and response(s) to the targeted therapies described in the Projects. PMTC will closely interact with the Biostatistics and Bioinformatics and Functional Genomic Cores for genomic and functional analyses. The PMTC proposes 2 Specific Aims in support of all 4 Projects: (1) Generate and characterize PTDX and derived PDO and (2) provide comprehensive planning, preparation and coordination of in vivo PDTX co-clinical studies. Finally, after development, the Core will distribute PDTX tumors to PIs for mechanistic studies as needed (Project 3). Project Summary/Abstract Page 640

联系PD/PI：Rimsza，丽莎Shared-Res-Core-003（458） 临床前模型和治疗核心（PMTC）将生成/组装和表征各种 患者来源的肿瘤异种移植物（PDTX）模型和患者来源的类器官（PDO）。我们将使用PDTX 用于进行项目1、2、3和4中描述的体内临床前动物研究的模型。这将允许 有效和一致的评价，在每一个新的治疗方法提出的疗效， 项目癌症转化研究已大大促进了人类肿瘤的证明， 可以作为异种移植物在免疫功能低下的小鼠中生长，并且PDTX的使用显著增加了 癌症生物学的公共知识，并提高了临床前评估和研究的可预测性 毒品从历史上看，高达85%的体外活性药物在人体研究中失败。更重要的是， PDTX被证明保持了原始患者肿瘤的许多特征，包括表达 表型，基因组景观和肿瘤异质性和内在特性，如他们的能力， 定植/扩散到特定器官。这允许设计和实现高度信息化的 临床前试验，能够预测个体癌症患者的反应。PDTX作为 可再生的，质量受控的组织资源，用于新治疗方案的临床前评价， 评估靶向治疗疗效的主要平台，在本项目中概述 当前应用。尽管许多PDTX已经从实体癌中建立，但来自血液系统的PDTX仍然存在。 疾病仍然很罕见，没有综合性的图书馆。在这里，我们将重点放在一代和 因此，本发明提供了用于表征来自DLBCL和T细胞淋巴瘤的PDTX的方法，这仍然是未满足的临床需求。是 现在认识到，在这一竞技场中，治疗成功率低主要是由于 这些肿瘤，以及在成熟T细胞肿瘤的情况下，缺乏“真正的”细胞系，或 可重复和信息丰富的小鼠模型。PDTX和衍生的2D/3D体外模型都将在分子水平上进行分析。 分析（WES/靶测序，总RNA-Seq和ERBBS）并使用功能方法验证。 临床前试验将使用一系列常规和新型化合物进行。PDTX尤其 通过使用PDO，可用于体内机制研究，并且来自这些研究的信息将 有助于理解生物学、分层标准和对靶向治疗的反应 项目中描述的。PMTC将与生物统计学和生物信息学密切互动， 用于基因组和功能分析的功能基因组核心。PMTC提出了两个具体目标， 支持所有4个项目：（1）生成和表征PTDX和衍生PDO，以及（2）提供 全面规划、准备和协调体内PDTX联合临床研究。最后经过 在开发过程中，核心将根据需要将PDTX肿瘤分发给PI进行机制研究（项目3）。 项目摘要/摘要第640页