University of Pennsylvania Patient-derived Xenograft Development and Trials Center

宾夕法尼亚大学患者来源的异种移植开发和试验中心

• 批准号: 10733231
• 负责人: MARTIN CARROLL
• 金额: $ 93.06万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733231
• 关键词: 15 year old; Acute Myelocytic Leukemia; Bioinformatics; Biology; Cancer cell line; Characteristics; Clear cell renal cell carcinoma; Clinical; Clinical Trials; Collection; Combined Modality Therapy; Communities; Core Facility; Dedications; Development; Disease; Glioblastoma; Goals; Human; Human Resources; Infection; Infection Control; Link; MDM2 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Menin; Modeling; Molecular; Multiple Myeloma; Mus; NCI Center for Cancer Research; Non-Malignant; Ovarian; Ovarian Clear Cell Tumor; Ovarian Serous Adenocarcinoma; Patients; Pennsylvania; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Pilot Projects; Primary carcinoma of the liver cells; Recording of previous events; Renal Cell Carcinoma; Reproducibility; Research; Research Personnel; Sampling; TP53 gene; Testing; Therapeutic; Tissue Banks; Universities; University resources; Work; Xenograft Model; Xenograft procedure; animal facility; bioinformatics infrastructure; burden of illness; cancer type; clinical implementation; experience; malignant breast neoplasm; member; mortality; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; phase 2 study; pre-clinical; precision oncology; rare cancer; response; skills; stem cells; targeted treatment; translational potential; treatment response; tumor

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.

项目摘要/摘要： 宾夕法尼亚大学PDX开发与治疗中心（UP-PDTC）的总体目标是 （i）利用PDX模型的翻译潜力来评估各种处理的反应 具有特定分子特征并与PDXNET合作以增强和扩展PDX的模型 研究社区的模型，目的是指导人类1/2阶段临床试验的发展 人类恶性肿瘤。由于PDX模型比细胞系更忠实地再现人类癌症，因此它们可以 有助于癌症精密医学的最终临床实施。 UP-PDTC是唯一的 由于upenn的PDX研究悠久的历史，因此被中毒为这项研究做出了贡献。 UP-PDTC会 包括4个核心和2个项目。这四个核心是：行政，PDX，飞行员项目和跨网络， 和生物信息学核心。管理核心将协调所有UP-PDTC活动。 PDX核心 基于Upenn的干细胞和异种移植核心设施的15年经验。 PDX核心 目前，使用PDX建模用于恶性和 非恶性疾病。 PDX核心的动物设施是由高度控制的专用的6间客房套件 具有全面感染控制措施的熟练PDX核心人员。使用这些措施，PDX 七年来，核心在殖民地没有产生重大感染。飞行员项目核心将采取 越来越多的合作者的优势来建造肝细胞癌（HCC）的组织库，清晰 细胞肾细胞癌（CCRCC），乳腺癌，胶质母细胞瘤和骨髓瘤。 UP-PDTC的主要目标是 开发和表征跨常见和稀有癌症类型的新模型，这些模型可以与 起源患者临床反应概况并与PDXNET共享。生物信息学核心利用 UPenn广泛的生物信息学基础设施，将与项目合作，以更严格 描述用于急性髓样白血病（AML）和卵巢癌的PDX建模。有两个项目。项目 一个由马丁·卡罗尔（Martin Carroll）博士执导，将重点放在急性髓样白血病上。项目1利用 世界上最大的可行，带注释的AML样品最大的组织库之一。目前这个薄纸库 从20年内收集的1700多名患者收集了3300多个收集 当前已描述的100多个模型。卡洛尔博士，与 PDX核心有悠久的发展和使用AML PDX模型来定义AML生物学和 对治疗的反应。项目2由Fiona Simpkins博士指导，并利用卵巢癌 研究中心肿瘤生物果收集。该系列已有15年的历史，也完全注释 包括140个特征良好的PDX模型。博士。卡洛尔和辛普金斯有丰富的经验 异种移植模型和使用异种移植模型都可以理解疾病生物学 并开发新的治疗方法来实施临床试验。在他们的项目中，他们提出了 两个离散的异种移植阶段2研究。卡洛尔博士将测试与 Menin抑制作用和Kat6a对AML分化和疾病伯恩的抑制作用。辛普金斯博士将学习 TP53野生型透明细胞卵巢癌（CCOC）和低级浆液卵巢癌（LGSOC）和 它们在PDX模型中对“ P53稳定器组合”​​（MDM2和XPO1抑制）的响应。两者都是卡洛尔博士 辛普金斯博士具有丰富的经验，将临床前的工作转移到人类的早期临床试验中， 我们预计这些异种移植阶段2（XP2）的研究将导致分子定义的1/2期人 研究。总体而言，UP-PDTC的独特资源应增强PDX模型的使用来稳健和 可再现的研究将导致人类的精确靶向治疗。