Washington University PDX Development and Trial Center

随着一些新的分子靶点的发现和抗癌药物数量的指数级增长， 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物（PDX）模型在药物测试中的独特优势， 个性化医疗，医生和研究人员在华盛顿大学医学院（WUSM）和 Siteman癌症中心一直在积极地生成和利用PDX模型进行癌症研究， 分子靶向药物的评价。在我们的实力和现有基础设施的基础上，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，以促进临床前测试在全国范围内的合作努力。 WU-PDTC内的PDX核心将开发和表征至少1000种新的无病原体PDX模型 在主要肿瘤类型中。PDX模型将使用以下方法进行基因组和表型表征： 最新的“组学技术，并使用最新的数据分析管道进行专业分析， 用于其他大型NCI项目。生物信息学核心将这些分析与临床 来自原始患者的注释，包括患者治疗史和肿瘤反应（目标1）。我们两 研究项目将使用单一药物和药物组合药物进行PDX临床试验 根据NCI-IND（目标2）。项目1将在100多个受试者中测试泛或β亚型特异性I类PI 3 K抑制剂。 乳腺PDX模型，而项目2将研究克服肿瘤内在和 在超过100个已经可用的胰腺PDX模型中，ERK抑制的外在机制。蛋白基因组学 作为表征PDX的更广泛努力的一部分， 模型，并进行临床相关性和治疗反应分析的生物信息学核心（目的 3）。所有相关信息，包括PDX模型的蛋白基因组学特征和治疗/缓解史， 将在PDXNet和PDMR-FNLCR可访问的专用关系数据库中进行跟踪。的 目的是确定ET-CTN人体临床试验的候选人。在目标4中，WU-PDTC将利用 现有的专业知识和计划，从NCI指定的综合Siteman癌症中心，研究所 临床和转化研究（ITCS），McDonnell基因组研究所，Mallinkrodt成像研究 中心和早期治疗性临床试验网络（ET-CTN），以支持开发和利用 PDX模型，与PDXNet的其他组件合作，测试和改善癌症治疗。 最后，WU-PDTC通过行政核心的协调，将支持试点研究项目 利用PDX资源，促进PDTC、PNMR-FNLCR和其他NCI之间的协作 程序.其目标是增加PDX临床试验中测试的药物谱，并改善药物的临床应用。 通过创新的Cross-PDXNet研究，提高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在推进PDX模型在临床前测试中的使用。

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.