Washington University PDX Development and Trial Center

项目摘要/摘要：总体 随着一些新的分子靶点的发现和抗癌药物数量的指数增加 为了设计合理的临床试验，优化临床前模型已成为当务之急。 认识到患者来源的异种移植(PDX)模型在药物测试和治疗中的独特优势 华盛顿大学医学院(WUSM)的个性化医学、医生和研究人员以及 西特曼癌症中心一直在积极地生成和利用PDX模型用于癌症研究和 分子靶向制剂的评价。基于我们的实力和现有的基础设施，我们建议 建立华盛顿大学PDX开发和试验中心(WU-PDTC)，作为PDXNet的一部分 计划，以在全国范围内合作努力促进临床前试验。 WU-PDTC中的PDX核心将开发和表征至少1000种新的无病原体PDX模型 主要的肿瘤类型。PDX模型将使用基因和表型表征 最新的组学技术，并使用最新的数据分析管道进行了专业分析 部署在其他大规模NCI项目中。生物信息学核心将把这些分析与临床相结合 原始患者的注解，包括患者治疗史和肿瘤反应(目标1)。我们的两个 研究项目将使用单一药物和使用药物的联合药物进行PDX临床试验 在NCI-IND(目标2)下。项目1将在100多个人中测试PAN或β亚型特异性I类PI3K抑制剂 乳房PDX模型，而项目2将研究克服肿瘤固有和 在100多个已有的胰腺PDX模型中抑制ERK的外部机制。蛋白质组学 临床反应数据将在这些模型中收集，作为表征PDX的更广泛努力的一部分 由生物信息学核心(AIM)建立模型并进行临床相关性和治疗反应分析 3)。所有相关信息，包括PDX模型的蛋白质基因组学特征和治疗/应答史， 将在PDXNet和PDMR-FNLCR可访问的专用关系数据库中进行跟踪。这个 目标是确定ET-CTN的人体临床试验候选者。在目标4中，WU-PDTC将利用 来自国家癌症研究所指定的综合西特曼癌症中心的现有专业知识和计划 临床和翻译研究(ITCS)，McDonnell基因组研究所，Mallinkrodt成像研究 中心和早期治疗临床试验网络(ET-CTN)，以支持开发和利用的目标 与PDXNet的其他组成部分合作，测试和改进癌症治疗的PDX模型。 最后，WU-PDTC将通过行政核心的协调，支持试点研究项目 利用PDX资源并促进跨PDTC、PNMR-FNLCR和其他NCI的协作 程序。其目标是增加在PDX临床试验中测试的药物的范围，并改善 通过创新的跨PDXNet研究，实现PDX模型的可靠性、有效性、实用性和标准化。 我们在生成和利用PDX模型、广泛的现有基础设施以及 强有力的机构承诺为成功的PDTC奠定了坚实的基础，这将有助于实现 NCI推动PDX模型在临床前试验中的使用。

Project Summary/Abstract: Overall With the discovery of a number of new molecular targets and exponential increase in the number of anti-cancer agents, it has become imperative to optimize preclinical models in order to design rational clinical trials. Recognizing the unique advantage of the patient-derived xenografts (PDXs) models in drug testing and personalized medicine, physicians and researchers at Washington University School of Medicine (WUSM) and the Siteman Cancer Center have been actively generating and utilizing PDX models for cancer research and the evaluation of molecularly targeted agents. Building on our strength and existing infrastructure, we propose to establish the Washington University PDX Development and Trial Center (WU-PDTC), as part of PDXNet program, to promote preclinical testing in a collaborative nation-wide effort. The PDX core within WU-PDTC will develop and characterize at least 1000 new pathogen-free PDX models across major tumor types. The PDX models will be genomically and phenotypically characterized using the latest `omics technologies and expertly analyzed using the most current data analysis pipelines that have been deployed for other large scale NCI programs. The Bioinformatics Core will integrate these analyzes with clinical annotation from the originating patient to include patient treatment history and tumor response (Aim 1). Our two research projects will conduct PDX clinical trials using single agent and combinational agents using drugs under NCI-IND (Aim 2). Project 1 will test pan- or beta isoform specific class I PI3K inhibitors in over 100 breast PDX models while Project 2 will study combinatorial approaches that overcome tumor intrinsic and extrinsic mechanisms to ERK inhibition in over 100 already available pancreatic PDX models. Proteogenomic and clinical response data will be collected in these models, as part of a broader effort of characterizing PDX models and conducting clinical correlation and treatment response analyses by the Bioinformatics Core (Aim 3). All relevant information, including proteogenomic features of PDX models and treatment/response history, will be tracked in a dedicated relational database that will be accessible to PDXNet and PDMR-FNLCR. The goal is to identify candidates for human clinical trials for the ET-CTN. In Aim 4, the WU-PDTC will leverage existing expertise and programs from the NCI-designated Comprehensive Siteman Cancer Center, Institute of Clinical and Translational Research (ITCS), McDonnell Genome Institute, Mallinkrodt Imaging Research Center, and Early Therapeutic Clinical Trials Network (ET-CTN) to support the goals of developing and utilizing PDX models to test and improve cancer treatment, in collaboration with other components of the PDXNet. Finally, WU-PDTC, through coordination by the Administration Core, will support pilot research projects utilizing the PDX resources and fostering collaboration across PDTCs, PNMR-FNLCR, and other NCI programs. The goal is to increase the spectrum of agents tested in PDX clinical trials and to improve the reliability, validation, utility, and standardization of PDX models through innovative Cross-PDXNet research. Our demonstrated capability in generating and utilizing PDX models, extensive existing infrastructure, and strong institutional commitment set a solid foundation for a successful PDTC that will help achieve goals set by NCI in advancing the use of PDX models in preclinical testing.