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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：
10437004
负责人：
Xiaonan Li
金额：
$ 60.88万
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/10437004
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 Investigation 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 Ursidae Family Xenograft Model Xenograft procedure animal facility base cancer therapy cell bank cell killing childhood cancer mortality clinically relevant cohort cost effective data mining 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 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.

本申请是为响应资助机会而准备的：NCI儿科体内测试项目