In vivo Drug Testing of Pediatric CNS Tumors Using Patient Derived Orthotopic Xenograft Models

使用患者来源的原位异种移植模型对儿童中枢神经系统肿瘤进行体内药物测试

• 批准号: 10667430
• 负责人: Xiaonan Li
• 金额: $ 53.67万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-14 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667430
• 关键词: Animal Model; Animals; Autopsy; Biological Assay; Biological Models; Brain; Brain Neoplasms; Breeding; Cancer Etiology; Cancer Patient; Cells; Central Nervous System Neoplasms; Childhood; Childhood Brain Neoplasm; Childhood Central Nervous System Neoplasm; Childhood Glioblastoma; Clinic; Clinical; Clinical Drug Development; Clinical Trials; Cryopreservation; DNA; DNA methylation profiling; Databases; Diagnosis; Diffuse intrinsic pontine glioma; Dose; Drug Screening; Ensure; Ependymoma; Faculty; Funding Opportunities; Gene Expression; Glioblastoma; Glioma; Goals; Grant; Histopathology; Human; Implant; In Vitro; Injections; Institution; Investigational Drugs; Laboratories; Location; Modeling; Molecular; Molecular Abnormality; Molecular Target; Mus; NOD/SCID mouse; New Agents; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Positioning Attribute; Preclinical Testing; Primary Neoplasm; RNA; Recurrent tumor; Relapse; Resistance; SCID Mice; Series; Serum-Free Culture Media; Specimen; System; Techniques; Testing; Time; Transplantation; Treatment Efficacy; Universities; Xenograft Model; Xenograft procedure; animal facility; cancer therapy; cell bank; cell killing; childhood cancer mortality; clinically relevant; cohort; cost effective; data mining; drug action; drug candidate; drug testing; efficacy evaluation; experience; implantation; in vivo; in vivo evaluation; medical schools; medulloblastoma; member; molecular modeling; molecular subtypes; mouse model; neoplastic cell; new therapeutic target; novel; novel anticancer drug; novel therapeutics; pre-clinical; programs; protein biomarkers; radioresistant; response; screening; success; therapeutic evaluation; therapeutic target; tumor; tumor xenograft; tumorigenic

This application is prepared in response to the funding opportunity: NCI Pediatric In Vivo Testing Program (U01), RFA-CA-20-034 to renew our existing PPTC UO1 grant. Specifically, we propose to continue the in vivo testing program for central nervous system (CNS) tumors using our panel of patient derived orthotopic xenograft (PDOX) models. Brain tumor is the leading cause of cancer-related death in children. One of the challenges in clinical drug development is how to effectively prioritize drug candidates to ensure clinical success in cancer patients. However, efforts in identifying new anti-cancer agents for that are most likely to be effective in the clinic have been blocked for many years due to the lack of clinically relevant and molecularly accurate model system. Fortunately, we have established a panel of 150 PDOX models of pediatric brain tumors through direct injection of patient tumor specimens into the brains of SCID mice. These PDOX models are shown to have replicated the histopathology and major genetic abnormalities of the original patient tumors even during serial sub-transplantations in vivo in mouse brains. They not only represent different clinical stage (i.e., at diagnosis, relapse and terminal/autopsy) but also replicate a broad spectrum of the newly identified molecular subtypes of nearly all types of pediatric brain tumors. The xenograft tumor cells can also be cryopreserved for sustained and on-demand supply of tumorigenic PDOX cells. This capacity combined with our optimized surgical procedure, with which we can implant up to 260 mice per day, makes it possible for us to test multiple (e.g., 6-10) drugs per year for every tumor type. Our objective is therefore to make use of this unique panel of PDOX models to examine therapeutic efficacy of new agents and to analyze mechanisms of action and therapy resistance in high grade glioma, medulloblastoma, ependymoma, DIPG and ATRT. Our hypothesis is that these patient-specific PDOX tumors will respond to anti-cancer therapies similarly to the corresponding human primary tumors, and the effective agents identified through this system would have better chances of clinical success. To test this hypothesis, we will perform a series of in vitro and in vivo assays to achieve the following aims: 1) to identify genetically accurate candidate PDOX models that bear the therapeutic target(s) of new investigational drugs through data mining of our mouse model molecular characterization databases; 2) to select the most responsive models through functional in vitro screening to determine time- and dose-responses; 3) to demonstrate therapeutic efficacy of new investigational drugs in multiple target-bearing PDOX models; and 4) to perform detailed analysis of cellular and molecular mechanisms of cell killing as well as the causes of therapy resistance both in vitro and in vivo. Our novel panel of PDOX mouse models represents a broad spectrum of genetic abnormalities of pediatric CNS tumors. All the assays are well established and routinely performed in our laboratory; we are uniquely positioned to accomplish the proposed drug studies in vivo. Our findings should provide strong preclinical evidence to support the initiation of clinical trials.

本申请是为了响应资助机会而准备的：NCI儿科体内测试计划 (U01)，RFA-CA-20-034更新我们现有的PPTC UO 1补助金。具体而言，我们建议继续体内 使用我们的一组患者来源的原位异种移植物进行中枢神经系统（CNS）肿瘤的测试程序 （PDOX）模型。脑肿瘤是儿童癌症相关死亡的主要原因。的挑战之一 在临床药物开发中，如何有效地优先考虑候选药物以确保临床成功， 癌症患者。然而，寻找新的抗癌药物的努力最有可能是有效的 由于缺乏临床相关和分子水平的研究， 精确的模型系统。幸运的是，我们已经建立了一组150个儿童脑PDOX模型， 通过将患者肿瘤标本直接注射到SCID小鼠的脑中来治疗肿瘤。这些PDOX型号 显示出复制了原始患者的组织病理学和主要遗传异常 甚至在小鼠脑中的体内连续亚移植期间也是如此。它们不仅代表着 临床阶段（即，在诊断，复发和终端/尸检），但也复制了一个新的广谱 鉴定了几乎所有类型小儿脑肿瘤的分子亚型。异种移植肿瘤细胞还可以 冷冻保存以持续和按需供应致瘤PDOX细胞。这种能力结合 通过我们优化的手术程序，我们每天可以植入多达260只小鼠， 用户测试多个（例如，6-10）药物每年每种肿瘤类型。因此，我们的目标是利用 这一独特的PDOX模型组用于检查新药物的治疗效果并分析机制 在高级别胶质瘤、髓母细胞瘤、室管膜瘤、DIPG和ATRT中的作用和治疗抗性。我们 假设是这些患者特异性PDOX肿瘤将对抗癌疗法产生类似的反应， 相应的人类原发性肿瘤，通过该系统鉴定的有效药物将具有 更好的临床成功率。为了验证这一假设，我们将进行一系列的体外和体内研究。 1）鉴定遗传上准确的候选PDOX模型， 通过对我们的小鼠模型分子的数据挖掘， 表征数据库; 2）通过功能性体外筛选选择最响应的模型， 确定时间和剂量反应; 3）证明新研究药物的疗效 在多个靶向PDOX模型中;以及4）进行细胞和分子的详细分析， 细胞杀伤机制以及体外和体内治疗抗性的原因。我们的新型 一组PDOX小鼠模型代表了儿科CNS的广泛遗传异常 肿瘤的所有的检测都是在我们的实验室中建立和常规进行的;我们是独一无二的 定位以完成所提出的体内药物研究。我们的研究结果应该提供强有力的临床前 支持启动临床试验的证据。

项目成果

Corrigendum to "Impact of SCID mouse gender on tumorigenicity, xenograft growth and drug-response in a large panel of orthotopic PDX models of pediatric brain tumors" [Cancer Lett. 493 (2020) 197-206].

“SCID 小鼠性别对儿科脑肿瘤原位 PDX 模型大型组中致瘤性、异种移植物生长和药物反应的影响”的更正 [Cancer Lett。

• DOI: 10.1016/j.canlet.2020.12.007
• 发表时间: 2021
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Qi,Lin;Kogiso,Mari;Du,Yuchen;Zhang,Huiyuan;Braun,FrankK;Huang,Yulun;Teo,Wan-Yee;Lindsay,Holly;Zhao,Sibo;Baxter,Patricia;Zhao,Xiumei;Yu,Litian;Liu,Zhigang;Zhang,Xingding;Su,Jack;Adesina,Adekunle;Yang,Jianhua;Chintagumpala
• 通讯作者: Chintagumpala

Evaluation of an EZH2 inhibitor in patient-derived orthotopic xenograft models of pediatric brain tumors alone and in combination with chemo- and radiation therapies.

• DOI: 10.1038/s41374-021-00700-8
• 发表时间: 2022-02
• 期刊: LABORATORY INVESTIGATION
• 影响因子: 5
• 作者: Qi, Lin;Lindsay, Holly;Kogiso, Mari;Du, Yuchen;Braun, Frank K;Zhang, Huiyuan;Guo, Lei;Zhao, Sibo;Injac, Sarah G;Baxter, Patricia A;Su, Jack Mf;Xiao, Sophie;Erickson, Stephen W;Earley, Eric J;Teicher, Beverly;Smith, Malcolm A;Li, Xiao-Nan
• 通讯作者: Li, Xiao-Nan

Impact of SCID mouse gender on tumorigenicity, xenograft growth and drug-response in a large panel of orthotopic PDX models of pediatric brain tumors.

• DOI: 10.1016/j.canlet.2020.08.035
• 发表时间: 2020-11-28
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Qi, Lin;Kogiso, Mari;Du, Yuchen;Zhang, Huiyuan;Braun, Frank K.;Huang, Yulun;Teo, Wan-Yee;Lindsay, Holly;Zhao, Sibo;Baxter, Patricia;Zhao, Xiumei;Yu, Litian;Liu, Zhigang;Zhang, Xingding;Su, Jack M. F.;Adesina, Adekunle;Yang, Jianhua;Chintagumpala, Murali;Perlaky, Laszlo;Man, Chris Tsz-Kwong;Lau, Ching C.;Li, Xiao-Nan
• 通讯作者: Li, Xiao-Nan

The 2021 WHO classification of central nervous system tumors: what neurologists need to know.

• DOI: 10.1097/wco.0000000000001109
• 发表时间: 2022-12-01
• 期刊: Current opinion in neurology
• 影响因子: 4.8