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:10160830
- 负责人:
- 金额:$ 33.73万
- 依托单位:
- 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:
- 关键词:3-DimensionalAliquotAllelesAnimal ModelBenchmarkingBiochemicalBiologicalBiological AssayBiologyBloodCell Culture TechniquesCell LineCellsCeramidesCharacteristicsChemotherapy-Oncologic ProcedureClassificationClinicalClinical DataClinical ResearchClinical TrialsCorrelative StudyCryopreservationCytogeneticsDNA LibraryDataDependenceDiseaseDoseDoxorubicinDrug KineticsEastern Cooperative Oncology GroupElderlyEpigenetic ProcessExhibitsFrequenciesGene FrequencyGenesGeneticGenetically Engineered MouseGerman populationGoalsGrantHematopoieticHeterogeneityHumanHuman ResourcesImmunocompetentIn VitroIncidenceInstitutesLabelLaboratoriesLuciferasesMalignant NeoplasmsMaximum Tolerated DoseMemorial Sloan-Kettering Cancer CenterMetabolismModelingMolecularMolecular ProfilingMonitorMorphologyMusMutateMutationMyeloproliferative diseaseNeoplasmsOutcomePathogenesisPatientsPhasePlasmaProbabilityProtocols documentationPublishingRegimenReproducibilityResearchResearch PersonnelResourcesReview CommitteeRoleSamplingServicesSpecimenSphingolipidsSystemTestingTherapeuticTherapeutic StudiesTimeTissue BanksToxic effectToxicokineticsTranslatingTransplantationXenograft ModelXenograft procedurebasebiobankchemotherapyclinical developmentclinical materialclinically relevantdesigndisorder subtypeefficacy clinical trialefficacy studyefficacy testinggenetic variantin vivoinsightleukemialeukemia tissue bankmolecular modelingmolecular subtypesmouse modelnanoliposomenovelnovel therapeuticspatient derived xenograft modelpre-clinicalpreclinical efficacypreclinical toxicityprogramsrepositorystandard of caresuccesstherapeutic developmenttherapeutic evaluationtumor
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.
项目概要
AML 是一种高度致命的肿瘤,其发病率不断增加,尽管我们的技术取得了进步
尽管对 AML 发病机制的了解不够,但它在很大程度上仍然是无法治愈的。 AML 是异构的,具有定义的子类型
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
注释和分子特征的原始人类 AML 样本和动物模型的机制 -
为基础的治疗研究。从资助第 1-5 年取得进展的许多例子都采用了这些
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。宾夕法尼亚州立大学癌症研究所 (PSCI) 银行的数据构成了大部分进展
本申请中描述。核心将通过添加临床前/临床分离株得到加强
纪念斯隆凯特琳癌症中心 (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 获取的标本。将提供分子分析样品
用于体外研究和 PDX 构建的项目和核心(目标 3)。目标 2) 评估毒性并
确定药物在体内的最大耐受剂量 (MTD) 和药代动力学 (PK)。动物模型
PSCI 已开展临床前毒性(剂量递增、MTD 和药代动力学)评估。结果
这一目标对于治疗方法的持续临床开发至关重要。目标 3) 开发和维护
用于测试程序衍生疗法的动物模型。该应用程序和我们发表的研究表明
在许多此类模型中获得的有希望的临床前数据。可移植的人类 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,允许体内肿瘤监测并提供
快速读取抗 AML 疗效 (PSCI)。本报告中提供了这些模型的大量数据
应用。此类模型中的临床前功效数据强调了评估神经酰胺纳米颗粒的前提
Ib/IIa 期临床试验中的脂质体 (CNL)、AraC 和 Venetoclax(项目 1,预 IND #142902,UVA 方案
审查委员会批准#5414,CAV 试验)。 Levine 博士(联合研究员;MSKCC)的基因小说
准确的 AML 模型提供分子定义的 AML 亚型的最先进模型。这些模型将
对于定义遗传驱动的鞘脂代谢改变和测试其功效至关重要
在所有项目 (MSKCC) 中制定治疗方案。最后,具有明确定义的主要 AML 的 PDX 模型
将用于验证 NRGS 宿主(PSCI 和 MSKCC)的研究结果。计划疗法的功效将是
与临床相关标准护理(SOC)化疗方案进行比较并结合。在
总的来说,动物建模和临床资源核心是一种独特且最先进的资源,
为所有项目提供转化新颖的生物学见解所需的动物模型和临床材料
和治疗进入临床研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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David F Claxton其他文献
David F Claxton的其他文献
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{{ truncateString('David F Claxton', 18)}}的其他基金
CLINICAL TRIAL: PI TRIAL OF IMMUNOSTIMULATION JVRS-100 FOR RELAPSED OR REFRACTOR
临床试验:免疫刺激 JVRS-100 用于复发或屈光不正患者的 PI 试验
- 批准号:
7951291 - 财政年份:2009
- 资助金额:
$ 33.73万 - 项目类别:
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