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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

基本信息

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
项目类别：
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

项目摘要

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，以更新我们现有的 PPTC UO1 拨款。具体来说，我们建议继续体内使用我们的患者来源的原位异种移植物组进行中枢神经系统 (CNS) 肿瘤测试计划（PDOX）模型。脑肿瘤是儿童癌症相关死亡的主要原因。挑战之一临床药物开发的关键是如何有效地确定候选药物的优先顺序，以确保临床成功癌症患者。然而，为此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，该技术在临床上的应用多年来一直受阻。准确的模型系统。幸运的是，我们已经建立了一组 150 个儿科 PDOX 模型通过将患者肿瘤标本直接注射到 SCID 小鼠的大脑中来研究肿瘤。这些 PDOX 模型被证明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大脑体内的连续亚移植过程中也能抑制肿瘤的发生。他们不仅代表着不同临床阶段（即诊断、复发和末期/尸检），而且还复制了广泛的新发现确定了几乎所有类型的儿童脑肿瘤的分子亚型。异种移植肿瘤细胞还可以冷冻保存以持续按需供应致瘤性 PDOX 细胞。这个容量加起来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，使得我们每年针对每种肿瘤类型测试多种（例如 6-10 种）药物。因此，我们的目标是利用这个独特的 PDOX 模型组用于检查新药的治疗效果并分析机制高级神经胶质瘤、髓母细胞瘤、室管膜瘤、DIPG 和 ATRT 中的作用和治疗耐药性。我们的假设这些患者特异性 PDOX 肿瘤对抗癌疗法的反应与相应的人类原发性肿瘤，通过该系统识别出的有效药物将具有临床成功的机会更大。为了验证这一假设，我们将进行一系列体外和体内实验检测以实现以下目标：1) 鉴定具有遗传准确性的候选 PDOX 模型通过对我们的小鼠模型分子的数据挖掘来确定新研究药物的治疗靶点表征数据库； 2）通过功能性体外筛选选择反应最灵敏的模型确定时间和剂量反应； 3）证明新研究药物的治疗效果在多个目标承载 PDOX 模型中； 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耐药的原因。我们的小说 PDOX 小鼠模型组代表了儿科中枢神经系统的广泛遗传异常肿瘤。所有检测均已在我们的实验室中建立并常规进行；我们是独一无二的定位于完成拟议的体内药物研究。我们的研究结果应该提供强有力的临床前研究支持启动临床试验的证据。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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
作者：
通讯作者：

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