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：
10579262
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/10579262
关键词：
Acceleration 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 candidate identification chemotherapy clinical care 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 preclinical development 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.

项目概要儿童实体瘤是一种罕见且高度异质性的癌症集合。对于许多亚型来说，进展过去 10 至 20 年间，新疗法的定义一直停滞不前。事实上，对于大多数此类肿瘤化疗仍然是主要的治疗形式，并且尚无靶向治疗。这缺乏进展可能至少部分归因于针对个体组织学开展临床试验的困难鉴于其稀有性，亚型。另一种方法是开发强大的临床前测试计划。目前，此类由于缺乏包含最先进技术的经过充分认证的模型，项目受到限制进行基因组和功能表征，并解决了缺乏治疗耐药性和功能性的良好模型的问题转移性疾病。在这里，我们汇集了两位具有互补专业知识的 PI 来开发新方法用于儿科实体瘤动物模型的验证和临床前使用。我们的重点是使用患者三种最常见组织型的衍生异种移植物：骨肉瘤、尤文肉瘤和横纹肌肉瘤。 PDX 模型特别适合研究高度异质性肿瘤，例如儿科实体瘤肿瘤。在目标 1 中，我们将开发新颖的先进 PDX 模型，其中包含两项关键创新：i) 利用用于基因询问的 CRISPR/CAS9 技术以及 ii) 自体和同种异体方法开发具有人类免疫系统的 PDX 模型 (hu-PDX)。在目标 2 中，我们将开发新颖的评估 PDX 模型与其肿瘤起源的相似性并评估人类的计算工具小鼠和小鼠间的进化可能会影响临床相关性。我们将与成员密切合作肿瘤模型论坛开发评分系统来评估这种相似性并使这些工具得到广泛应用可供建模社区使用。在目标 3 中，我们将评估人-小鼠实验中的肿瘤内异质性以及使用单细胞 RNAseq 的 PDX 模型的小鼠-小鼠进化。我们期望工具和模型这里开发的将广泛适用于其他 PDX 模型，我们开发的具体模型将帮助促进临床前研究。我们将使所有工具和模型广泛可供研究使用社区。