University of Pennsylvania Patient-derived Xenograft Development and Trials Center

项目摘要/摘要： 宾夕法尼亚大学PDX开发和治疗中心(UP-PDTC)的总体目标是 为了(I)开发PDX模型的翻译潜力，以评估不同治疗方案的反应 具有特定分子特征的模型和(Ii)与PDXNet合作以增强和扩展PDX的使用 模型给研究界，目标是指导人类1/2期临床试验的开发 人类的恶性肿瘤。由于PDX模型比细胞系更忠实地复制人类癌症，它们可以 为癌症精准医学的最终临床实施贡献力量。UP-PDTC是唯一的 由于宾夕法尼亚大学PDX研究的悠久历史，准备为此类研究做出贡献。UP-PDTC将 包括4个核心和2个项目。这四个核心是：管理、PDX、试点项目和跨网络， 和一个生物信息学核心。行政核心将协调所有UP-PDTC活动。PDX核心 在宾夕法尼亚大学干细胞和异种移植核心设施中积累了15年的经验。PDX核心 目前每月向宾夕法尼亚大学的研究人员提供900多只小鼠，使用PDX对恶性肿瘤和 非恶性疾病。PDX Core的动物设施是一个专门的6个房间的套房，由High 熟练的PDX核心人员，具备全面的感染控制措施。使用这些措施，PDX 科尔已经七年没有在这个殖民地受到重大感染了。核心将采取的试点项目 越来越多的合作者在建立肝细胞癌组织库方面的优势，Clear 肾细胞癌、乳腺癌、胶质母细胞瘤和骨髓瘤。UP-PDTC的一个主要目标是 开发和表征常见和罕见癌症类型的新模型，这些模型可以与 原始患者临床反应档案并与PDXNet共享。生物信息学核心利用 并将与这些项目合作，以更严格地 描述急性髓系白血病(AML)和卵巢癌的PDX模型。有两个项目。项目 其中一部由马丁·卡罗尔博士执导，将专注于急性髓系白血病。项目1利用 世界上最大的可存活的、有完整注释的急性髓细胞白血病样本组织库之一。这个组织银行目前 20年来收集了1700多名患者的3300多份标本，其中包括40多份PDX初级移植物 目前有100多种型号可供选择，这些型号已经描述过了。卡罗尔博士，与世界卫生组织 PDX Core在开发和使用AML PDX模型以定义AML生物学和 对治疗的反应。项目2由菲奥娜·辛普金斯博士执导，利用卵巢癌 研究中心肿瘤生物信托收藏。这本收藏已经有15年的历史了，也有完整的注释和 包括140个特点良好的PDX型号。卡罗尔博士和辛普金斯博士在 异种移植模型和利用异种移植模型来理解疾病生物学 并开发新的治疗方法，用于临床试验。在他们的项目中，他们提出 两项离散的异种移植第二阶段研究。卡罗尔博士将测试一种联合治疗方法的效果 Menin抑制和KAT6A抑制对AML分化和疾病负担的影响。辛普金斯博士将研究 TP53野生型透明细胞卵巢癌和低级别浆液性卵巢癌 它们在PDX模型中对“P53稳定剂组合”(MDM2和XPO1抑制)的反应。两位卡罗尔博士 辛普金斯博士在将临床前工作转移到人类早期临床试验和 我们预计，这些异种移植2期(XP2)研究将导致分子定义的人类1/2期 学习。总体而言，伙伴关系--伙伴关系的独特资源应加强对伙伴关系模型的使用，以实现稳健和 可重复的研究将导致在人类身上进行精确的靶向治疗。

Project Summary/Abstract: The overall goal of the University of Pennsylvania PDX Development and Therapeutics Center (UP-PDTC) is to (i) exploit the translational potential of PDX models for evaluating the response of various treatments in models with specific molecular characteristics and to (ii) work with PDXNet to enhance and extend use of PDX models to the research community with the goal to guide development of human Phase 1/2 clinical trials for human malignancies. As PDX models more faithfully reproduce human cancer than cell lines, they can contribute to the ultimate clinical implementation of cancer precision medicine. The UP-PDTC is uniquely poised to contribute to such research due to the long history of PDX research at UPENN. The UP-PDTC will comprise 4 Cores and 2 projects. The four Cores are: Administrative, PDX, Pilot Projects and Trans-Network, and a Bioinformatics Core. The Administrative Core will coordinate all UP-PDTC activities. The PDX Core builds on 15 years of experience within the Stem Cell and Xenograft Core facility of UPENN. The PDX Core currently provides over 900 mice per month to investigators at UPENN using PDX modeling for malignant and non-malignant disease. The animal facility of the PDX Core is a dedicated 6 room suite controlled by highly skilled PDX Core personnel with comprehensive infection control measures. Using these measures, the PDX Core has not had a significant infection in the colony in seven years. The Pilot Projects Core will take advantage of a growing group of collaborators to build tissue banks for hepatocellular carcinoma (HCC), clear cell renal cell carcinoma (ccRCC), breast cancer, glioblastoma, and myeloma. A major goal of the UP-PDTC is to develop and characterize new models across common and rare cancer types that can be linked with the originating patient clinical response profile and shared with PDXNet. The Bioinformatics Core takes advantage of the extensive Bioinformatics infrastructure at UPENN and will work with the Projects to more rigorously describe PDX modeling for acute myeloid leukemia (AML) and ovarian cancer. There are two projects. Project One is directed by Dr. Martin Carroll and will focus on acute myeloid leukemia. Project 1 takes advantage of one of the largest tissue banks of viable, fully annotated AML samples in the world. This tissue bank currently has over 3300 collections from over 1700 patients collected over 20 years including over 40 PDX primograft models currently available of over 100 that have been described. Dr. Carroll, working with members of the PDX Core, has a long history of developing and using the AML PDX model to define AML biology and responses to therapy. Project 2 is directed by Dr. Fiona Simpkins and takes advantage of the Ovarian Cancer Research Center Tumor BioTrust Collection. This collection is fifteen years old, also fully annotated and includes 140 well characterized PDX models. Drs. Carroll and Simpkins, have extensive experience in xenotransplantation models and in the use of xenotransplantation models to both understand disease biology and develop new therapeutic approaches for implementation in clinical trials. In their projects, they propose two discrete xenotransplantation Phase 2 studies. Dr. Carroll will test the effects of a combined therapy with Menin inhibition and KAT6A inhibition on AML differentiation and disease burden. Dr. Simpkins will study TP53 wild type clear cell ovarian carcinoma (CCOC) and low-grade serous ovarian carcinoma (LGSOC) and their response in PDX models to a “p53 stabilizer combination” (MDM2 and XPO1 inhibition). Both Dr. Carroll and Dr. Simpkins have significant experience moving pre-clinical work into human early-stage clinical trials and we anticipate that these xenotransplant phase 2 (XP2) studies will lead to molecular defined Phase 1/2 human studies. Overall, the unique resources of the UP-PDTC should enhance the use of PDX models for robust and reproducible studies that will lead to precision targeted therapeutics in humans.