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Preclinical Models and Therapeutics Core

临床前模型和治疗核心

基本信息

批准号：
10237167
负责人：
Giorgio Inghirami
金额：
$ 14.79万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-19 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237167
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&apos 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

项目摘要

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、Lisa Shared-Res-Core-003 (458) 临床前模型和治疗核心 (PMTC) 将生成/组装并表征广泛的阵列患者来源的肿瘤异种移植（PDTX）模型和患者来源的类器官（PDO）。我们将使用PDTX 模型进行项目 1、2、3 和 4 中描述的体内临床前动物研究。这将允许对每个研究中提出的新治疗方法的功效进行有效和一致的评估项目。人类肿瘤的证明极大地促进了转化癌症研究可以在免疫功能低下的小鼠中作为异种移植物生长，并且 PDTX 的使用显着增加了公众对癌症生物学的了解，并提高了研究的临床前评估和可预测性药物。从历史上看，高达85%的具有体外活性的药物在人体研究中都失败了。更重要的是， PDTX 被证明可以保持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以及内在特性，例如它们的能力定殖/传播到特定器官。这允许设计和实现信息丰富的临床前试验，能够预测个体癌症患者的反应。 PDTX 充当可再生、质量受控的组织资源，用于新治疗方案的临床前评估，并将评估靶向治疗功效的主要平台，在本项目的项目中概述当前的应用程序。尽管许多PDTX是从实体癌中建立的，但PDTX是从血液学中建立的疾病仍然很少见，并且不存在综合图书馆。这里我们将重点关注生成和 DLBCL 和 T 细胞淋巴瘤的 PDTX 特征，这仍然是一个未满足的临床需求。这是现在认识到，这一领域的治疗效果不佳很大程度上是由于复杂的异质性这些肿瘤，以及在成熟 T 细胞肿瘤的情况下，缺乏“真正的”细胞系或可重复且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使用功能方法进行分析（WES/目标测序、总 RNA-Seq 和 ERBBS）并进行验证。将使用一系列传统和新型化合物进行临床前测试。 PDTX 特别是通过使用 PDO 对体内机制研究很有用，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。 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 2 个具体目标支持所有 4 个项目：(1) 生成并表征 PTDX 和派生 PDO，以及 (2) 提供体内 PDTX 联合临床研究的全面规划、准备和协调。最后，之后开发过程中，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