Development of Advanced Preclinical Models for Pediatric Solid Tumors

儿科实体瘤先进临床前模型的开发

• 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
• 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

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.

项目总结 儿童实体瘤是一种罕见且高度异质性的肿瘤。对于许多子类型，进度 在过去的10-20年里，对新疗法的定义一直停滞不前。事实上，对于这些肿瘤中的大多数 化疗仍然是主要的治疗形式，没有针对性的治疗方法。这 缺乏进展可能至少部分是由于为个别组织学开展临床试验的困难。 鉴于它们的稀有性，亚型。另一种选择是开发一个强大的临床前测试计划。目前，这样的 由于缺乏结合了最先进技术的具有良好资质的模型，这些项目受到限制 用于基因组和功能表征，并解决缺乏良好的治疗耐药和 转移性疾病。在这里，我们将两个具有互补专业知识的PI聚集在一起，以开发新的方法 用于儿童实体瘤动物模型的验证和临床前使用。我们的重点是使用耐心- 用于三种最常见的组织类型的异种移植：骨肉瘤、尤文肉瘤和横纹肌肉瘤。 PDX模型特别适合研究高度不均匀的肿瘤，如儿科实体瘤 肿瘤。在目标1中，我们将开发新型高级PDX模型，其中包含两个关键创新：i)利用 CRISPR/Cas9遗传查询技术和二)自体和同种异体方法 利用人体免疫系统建立PDX模型(HU-PDX)。在目标2中，我们将开发小说 用于评估PDX模型与其来源肿瘤的相似性以及评估人类- 可能影响临床相关性的老鼠和老鼠-老鼠进化。我们将与以下组织的成员密切合作 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 可供模特界使用。在目标3中，我们将评估人类-小鼠肿瘤内的异质性。 以及使用单细胞RNAseq的PDX模型的小鼠-小鼠进化。我们希望这些工具和模型 在这里开发的将广泛适用于其他PDX型号，我们开发的特定型号将 帮助促进临床前研究。我们将使所有工具和模型广泛地供研究人员使用 社区。