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Tissue Repository and Animal Models Core

组织存储库和动物模型核心

基本信息

批准号：
10430094
负责人：
David F Claxton
金额：
$ 33.05万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-10 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10430094
关键词：
3-Dimensional Aliquot Alleles Animal Model Benchmarking Biochemical Biological Biological Assay Biology Blood Cell Culture Techniques Cell Line Cells Ceramides Characteristics Chemotherapy-Oncologic Procedure Classification Clinical Clinical Data Clinical Research Clinical Trials Correlative Study Cryopreservation Cytogenetics DNA Library Data Dependence Disease Dose Doxorubicin Drug Kinetics Eastern Cooperative Oncology Group Elderly Epigenetic Process Exhibits Frequencies Gene Frequency Genes Genetic Genetically Engineered Mouse German population Goals Grant Hematopoietic Heterogeneity Human Human Resources Immunocompetent In Vitro Incidence Institutes Label Laboratories Luciferases Malignant Neoplasms Maximum Tolerated Dose Memorial Sloan-Kettering Cancer Center Metabolism Modeling Molecular Molecular Profiling Monitor Morphology Mus Mutate Mutation Myeloproliferative disease Neoplasms Outcome Pathogenesis Patients Phase Plasma Probability Protocols documentation Publishing Regimen Reproducibility Research Research Personnel Resources Review Committee Role Sampling Services Specimen Sphingolipids System Testing Therapeutic Therapeutic Studies Time Tissue Banks Toxic effect Toxicokinetics Translating Transplantation Xenograft Model Xenograft procedure base biobank chemotherapy clinical development clinical material clinically relevant design disorder subtype efficacy clinical trial efficacy study efficacy testing genetic variant in vivo insight leukemia leukemia tissue bank molecular modeling molecular subtypes mouse model nanoliposome novel novel therapeutics patient derived xenograft model pre-clinical preclinical efficacy preclinical toxicity programs repository standard of care success therapeutic development therapeutic evaluation tumor

项目摘要

PROJECT SUMMARY AML is a highly lethal neoplasm, which is increasing in incidence, and in spite of advances in our understanding of AML pathogenesis, it is still largely incurable. AML is heterogeneous, with subtypes defined by clinical, morphologic, cytogenetic, and molecular characteristics. This core provides viable, clinically annotated, and moleculary characterized primary human AML samples and animal models for mechanism- based therapeutic studies. Numerous examples of progress from grant years 1-5 have employed these resources. This Core will pursue the following Specific Aims: Aim 1) Expand, maintain, and characterize leukemia tissue banks. Data from the Penn State Cancer Institute (PSCI) Bank form much of the progress described in this application. The Core will be strengthened by the addition of preclinical/clinical isolates from Memorial Sloan Kettering Cancer Center (MSKCC). Our bank will be expanded through inclusion of clinical trial specimens acquired from Project 1 (CAV trial) and ECOG. Molecularly profiled samples will be made available to Projects and Cores for in vitro study and PDX construction (Aim 3). Aim 2) Assess the toxicities and determine the Maximum Tolerated Dose (MTD) and pharmacokinetics (PK) of agents in vivo. Animal models for preclinical toxicity (dose escalation, MTD and pharmacokinetics) assessment are in place at PSCI. Results from this Aim are critical for continued clinical development of therapeutics. Aim 3) Develop and maintain animal models for testing program-derived therapies. This application and our published studies demonstrate promising preclinical data acquired in a number of such models. Transplantable human AML cell line models labelled with luciferase and YFP/RFP grown as NRG xenografts allow in vivo tumor monitoring and provide rapid readout of anti-AML efficacy (PSCI). Considerable data are provided with these models in this application. Pre-clinical efficacy data in such models underscore the premise of evaluating ceramide nano- liposome (CNL), AraC and venetoclax in a phase Ib/IIa clinical trial (Project 1, pre-IND #142902, UVA Protocol Review Committee Approval #5414, CAV trial). Dr. Levine's (co-investigator; MSKCC) novel genetically accurate AML models provide state-of-the-art models of molecularly defined AML subtypes. These models will be critical in defining genetically-driven alterations in sphingolipid metabolism and for testing the efficacy of Program therapeutic regimens in all Projects (MSKCC). Finally, PDX models with well-defined primary AMLs will be used to validate findings in NRGS hosts (PSCI and MSKCC). Efficacy of Program therapeutics will be compared to and combined with clinically relevant standard-of-care (SOC) chemotherapy regimens. In aggregate, the Animal Modeling and Clinical Resources Core is a unique and state-of-the-art resource which provides all Projects with animal models and the clinical material needed to translate novel biologic insights and therapeutics into clinical studies.

项目摘要 AML是一种高度致命的肿瘤，其发病率正在增加，尽管我们的研究取得了进展，尽管对AML发病机制的了解不多，但它在很大程度上仍然是不可治愈的。AML是异质性的，定义了亚型通过临床、形态学、细胞遗传学和分子特征。该核心提供了可行的，临床上注释和分子表征的原发性人AML样品和动物模型，基于治疗研究。许多例子的进展，从赠款年1-5已采用这些资源该核心将追求以下具体目标：目标1）扩展、维护和表征白血病组织库来自宾夕法尼亚州立癌症研究所（PSCI）银行的数据构成了大部分进展在本申请中描述。将通过添加来自以下菌株的临床前/临床分离株来加强核心 Memorial Sloan Kettering Cancer Center（MSKCC）我们的银行将通过纳入临床试验来扩大规模从项目1（CAV试验）和ECOG获得的标本。将提供分子特征样本用于体外研究和PDX构建的项目和核心（目标3）。目的2）评估毒性和确定体内药剂的最大耐受剂量（MTD）和药代动力学（PK）。动物模型临床前毒性（剂量递增、MTD和药代动力学）评估在PSCI进行。结果从这个目的是至关重要的治疗的持续临床发展。目标3）开发和维护用于测试程序衍生疗法的动物模型。这项申请和我们发表的研究表明，在许多这样的模型中获得的有希望的临床前数据。可移植的人AML细胞系模型用荧光素酶和YFP/RFP标记，作为NRG异种移植物生长，允许体内肿瘤监测，快速读出抗AML功效（PSCI）。在这篇文章中，这些模型提供了相当多的数据。应用程序.这些模型中的临床前疗效数据强调了评估神经酰胺纳米脂质体（CNL）、AraC和维奈托克的Ib/IIa期临床试验（项目1，pre-IND #142902，UVA方案审查委员会批准编号5414，CAV试验）。Levine博士（共同研究者; MSKCC）的新基因精确的AML模型提供了分子定义的AML亚型的最新模型。这些模型将在定义鞘脂代谢中遗传驱动的改变和测试在所有项目中规划治疗方案（MSKCC）。最后，具有明确定义的原发性AML的PDX模型将用于验证NRGS主机（PSCI和MSKCC）中的发现。计划治疗的有效性将是与临床相关标准治疗（SOC）化疗方案相比并与之联合。在总的来说，动物建模和临床资源核心是一个独特的和最先进的资源，为所有项目提供动物模型和转化新生物学见解所需的临床材料和治疗学应用到临床研究中。