Development of Advanced Preclinical Models for Pediatric Solid Tumors

儿科实体瘤先进临床前模型的开发

基本信息

批准号：
10356873
负责人：
DAVID H HAUSSLER
金额：
$ 58.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-05 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10356873
关键词：
Advanced Development Allogenic Alveolar Animal Model Autologous Biological Biological Models CRISPR screen CRISPR/Cas technology Cells Childhood Solid Neoplasm Clinical Clinical Trials Clonal Evolution Collaborations Collection Combined Modality Therapy Communities Computational Biology Computing Methodologies Credentialing Data Set Development Disease Drug Targeting Drug resistance Environment Evolution Ewings sarcoma Gene Cluster Gene Expression Generations Genes Genetic Genetic Transcription Genomic approach Genomics Goals Heterogeneity Histologic Human Immune Immune system Immunocompetent Immunocompromised Host Immunogenomics Individual Malignant Childhood Neoplasm Malignant Neoplasms Mammalian Cell Methods Modeling Molecular Mus Oncology Pathway interactions Patients Pediatric Oncologist Phenotype Pre-Clinical Model Preclinical Testing Primary Neoplasm Rare Diseases Reagent Research Research Personnel Resistance Resolution Rhabdomyosarcoma System Technology Testing Translating Validation Work cancer genomics chemotherapy clinical care clinical development clinically relevant computerized tools data sharing drug testing early phase clinical trial functional genomics genetic analysis genetic technology genome sequencing genomic tools innovation member model development novel novel strategies novel therapeutics osteosarcoma patient derived xenograft model pediatric patients pre-clinical pre-clinical research programs response single-cell RNA sequencing targeted treatment therapy design therapy resistant tool transcriptome sequencing translational scientist treatment response tumor tumor heterogeneity whole genome

项目摘要

PROJECT SUMMARY Pediatric solid tumors are a rare and highly heterogeneous collection of cancers. For many subtypes, progress in defining novel therapies has stalled over the last 10-20 years. Indeed, for most of these tumors chemotherapy continues to be the primary form of treatment and targeted therapies are not available. This lack of progress is likely due at least in part to the difficulty in developing clinical trials for individual histologic subtypes given their rarity. An alternative is to develop a robust preclinical testing program. Currently, such programs are limited by the lack of well-credentialed models that incorporate the most advanced technologies for genomic and functional characterization and do to the lack of good models for therapy-resistant and metastatic disease. Here we bring together two PIs with complimentary expertise to develop new approaches for validation and preclinical use of pediatric solid tumor animal models. Our focus is on the use of patient- derived xenografts for three most common histotypes: osteosarcoma, ewing sarcoma and rhabdomyosarcoma. PDX models are particularly well suited for studying highly heterogeneous tumors such as pediatric solid tumors. In Aim 1, we will develop novel advance PDX models that incorporate two key innovations: i) utilization of CRISPR/CAS9 technology for genetic interrogation and ii) autologous and allogeneic approaches for development of PDX models with a human immune system (hu-PDX). In Aim 2, we will develop novel computational tools to assess the similarity of PDX models to their tumor of origin and to evaluate human- mouse and mouse-mouse evolution which may impact clinical relevance. We will work closely with members of the Oncology Models Forum to develop scoring systems to assess this similarity and make these tools widely available to the modeling community. In Aim 3, we will evaluate intratumor heterogeneity during human-mouse and mouse-mouse evolution of PDX models using single cell RNAseq. We expect that the tools and models developed here will be widely applicable to other PDX models and that the specific models we develop will help facilitate preclinical research. We will make all tools and models widely accessible to the research community.

项目摘要小儿实体瘤是一种罕见且高度异质的癌症。对于许多亚型，进度在定义新的疗法中，过去10 - 20年一直停滞不前。确实，对于大多数这些肿瘤化学疗法仍然是治疗的主要形式，并且没有靶向疗法。这缺乏进步可能至少部分是由于难以开发单个组织学的临床试验亚型鉴于它们的稀有性。另一种选择是制定强大的临床前测试程序。目前，这样程序受到缺乏合并最先进技术的良好模型的限制用于基因组和功能表征，并为缺乏抗治疗的良好模型和转移性疾病。在这里，我们将两个PI和免费专业知识汇集在一起，以开发新方法用于验证和临床前使用小儿实体瘤动物模型。我们的重点是使用患者针对三种最常见的组织型的衍生异种移植物：骨肉瘤，尤因肉瘤和横纹肌肉瘤。 PDX模型特别适合研究高度异质肿瘤，例如小儿固体肿瘤。在AIM 1中，我们将开发新颖的Advance PDX模型，结合了两个关键创新：i）利用率 CRISPR/CAS9技术用于遗传审查和ii）自体和同种异体方法具有人类免疫系统（HU-PDX）的PDX模型的开发。在AIM 2中，我们将开发小说计算工具评估PDX模型与其原籍肿瘤的相似性并评估人类小鼠和小鼠小鼠的进化可能会影响临床相关性。我们将与肿瘤学模型论坛开发评分系统以评估这种相似性并广泛使这些工具广泛可用于建模社区。在AIM 3中，我们将评估人鼠期间的肿瘤内异质性使用单细胞RNASEQ的PDX模型的小鼠小鼠演变。我们希望工具和模型这里开发的将广泛适用于其他PDX模型，我们开发的特定模型将有助于促进临床前研究。我们将使所有工具和模型都可以广泛访问社区。