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.

项目概要/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 （i）利用PDX模型的翻译潜力，评估各种治疗的反应， 具有特定分子特征的模型，并（ii）与PDXNet合作，以增强和扩展PDX的使用 模型，以指导人类1/2期临床试验的发展， 人类恶性肿瘤由于PDX模型比细胞系更忠实地复制人类癌症， 有助于癌症精准医疗的最终临床实施。UP-PDTC是独一无二的 由于宾夕法尼亚大学PDX研究的悠久历史，我们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：行政、PDX、试点项目和跨网络， 和生物信息学核心行政核心将协调UP-PDTC的所有活动。PDX核心 建立在15年的经验，在干细胞和异种移植核心设施的宾夕法尼亚大学。PDX核心 目前每月向UPENN的研究人员提供900多只小鼠， 非恶性疾病。PDX核心的动物设施是一个专用的6室套房，由高度控制 熟练的PDX核心人员，采取全面的感染控制措施。通过这些措施，PDX 七年来，核心在殖民地没有发生过重大感染。试点项目核心将采取 越来越多的合作者建立肝细胞癌（HCC）组织库的优势，明确 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 开发和表征常见和罕见癌症类型的新模型，这些模型可能与 创建患者临床应答特征并与PDXNet共享。生物信息学核心利用 广泛的生物信息学基础设施在宾夕法尼亚大学，并将与项目，更严格地 描述了用于急性髓性白血病（AML）和卵巢癌的PDX建模。有两个项目。项目 其中一项由马丁·卡罗尔博士指导，重点关注急性骨髓性白血病。项目1利用 世界上最大的有活力的、完全注释的AML样本组织库之一。这个组织库目前 20年来收集了1700多名患者的3300多份标本，包括40多份PDX原代移植物 目前已有超过100种模型被描述。卡罗尔博士与 PDX Core在开发和使用AML PDX模型来定义AML生物学方面有着悠久的历史， 对治疗的反应。项目2是由菲奥娜Replikins博士和利用卵巢癌的优势， 研究中心肿瘤生物信托收集。这是十五岁的收集，也充分注释， 包括140个充分表征的PDX模型。卡罗尔和Replikins博士在以下方面拥有丰富的经验： 异种移植模型和异种移植模型的使用，以了解疾病生物学 并开发新的治疗方法用于临床试验。在他们的项目中，他们建议 两项独立的异种移植II期研究。卡罗尔医生将测试联合治疗的效果， Menin抑制和KAT 6A抑制对AML分化和疾病负荷的影响。Replikkins博士将研究 TP 53野生型透明细胞卵巢癌（CCOC）和低级别浆液性卵巢癌（LGSOC），以及 在PDX模型中，它们对“p53稳定剂组合”（MDM 2和XPO 1抑制）的反应。卡罗尔医生 Replikins博士在将临床前工作转移到人类早期临床试验方面有着丰富的经验， 我们预计这些异种移植2期（XP 2）研究将导致分子定义的1/2期人类 问题研究总的来说，UP-PDTC的独特资源应该加强PDX模型的使用， 可重复的研究，将导致精确的靶向治疗在人类。