Tissue Repository and Animal Models Core

项目总结 AML是一种高度致命的肿瘤，其发病率正在上升，尽管在我们的 对AML发病机制的了解，在很大程度上仍是不治之症。AML是异类的，已定义子类型 根据临床、形态、细胞遗传学和分子特征。这个核心在临床上提供了可行的 注释和分子特征的原始人类急性髓细胞白血病样本和动物模型的机制- 以治疗性研究为基础。从第一年到第五年的许多进展的例子都采用了这些 资源。该核心将追求以下具体目标：目标1)扩展、维护和特色化 白血病组织库。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 在本申请中描述的。核心将通过增加临床前/临床分离株而得到加强 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获得的标本。分子图谱样本将可供使用 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 测定药物在体内的最大耐受量(MTD)和药代动力学(PK)。动物模型 对于临床前毒性(剂量递增、MTD和药代动力学)，PSCI已经到位。结果 从这一目标出发，对于治疗学的持续临床发展至关重要。目标3)开发和维护 用于测试程序化疗法的动物模型。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了有希望的临床前数据。可移植的人急性髓系白血病细胞系模型 用荧光素酶和生长为NRG的YFP/RFP标记的异种移植瘤允许体内肿瘤监测和提供 快速读出抗AML疗效(PSCI)。这些模型提供了大量的数据。 申请。这些模型的临床前疗效数据强调了评价神经酰胺纳米药物的前提。 Ib/IIa期临床试验中的脂质体(CNL)、AraC和万乃馨(项目1，Pre-IND#142902，紫外线方案 审查委员会批准编号5414，CAV试验)。莱文博士(合作者；MSKCC)的基因小说 准确的AML模型提供了分子定义的AML亚型的最先进模型。这些型号将 在确定鞘磷脂代谢的遗传驱动的变化和测试 在所有项目中规划治疗方案(MSKCC)。最后，具有定义良好的主AML的PDX模型 将用于验证NRGS主机(PSCI和MSKCC)中的调查结果。程序治疗学的疗效将是 与临床相关的标准护理(SOC)化疗方案进行比较并结合使用。在……里面 集合，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临床材料，以转化新的生物学见解 和治疗学进入临床研究。

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.