New models and therapeutic approaches in alveolar rhabdomyosarcoma

肺泡横纹肌肉瘤的新模型和治疗方法

基本信息

批准号：
9899960
负责人：
David Michael Langenau
金额：
$ 38.54万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899960
关键词：
Adult Affect Alveolar Rhabdomyosarcoma Animal Model Automobile Driving Biological Models Biology CRISPR/Cas technology Cell Count Cell physiology Cells Child Chromosomal translocation Clinical Complex Development Disease Drug Screening Embryonal Rhabdomyosarcoma Event Experimental Animal Model FDA approved FOXO1A gene Gene Fusion Genes Goals Growth Head Human Human Cell Line Human Genetics Image Label Lead Malignant Neoplasms Modeling Molecular Mus Mutation Neoplasm Metastasis Oncogenic Outcome PAX3 gene PAX7 gene Pathway interactions Patients Pharmaceutical Preparations Predisposition Relapse Research Rhabdomyosarcoma Role Survival Rate Technology Testing Therapeutic Time United States Validation Work Xenograft Model Xenograft procedure Zebrafish cell type childhood sarcoma experimental study imaging approach imaging modality in vivo in vivo Model innovation malignant muscle neoplasm neoplastic cell novel novel therapeutics outcome forecast preclinical efficacy sarcoma screening success survival outcome targeted treatment therapeutic development tool development transcription factor translational impact tumor tumor growth

项目摘要

PROJECT SUMMARY (30 lines) Alveolar rhabdomyosarcoma (ARMS) is a common and aggressive muscle cancer that affects hundreds of children annually in the United States. ARMS are pathognomonic with oncogenic chromosomal translocations between the PAX genes and the fork-head transcription factor (FOXO1). Yet, the pathways that the PAX3/7- FOXO1 transcription factors modulate, the tumor cells of origin, and the therapeutic vulnerabilities that arise in ARMS cells is still unclear, largely due to lack of precision animal models that accurately recapitulate the same translocation fusion events found in human ARMS. The long-term goal of our work is to uncover therapeutically relevant pathways that drive ARMS growth. The overall objective of this application is to develop zebrafish models of ARMS to identify therapeutic vulnerabilities that can be exploited clinically. Our central hypothesis is that worse survival outcomes in PAX3-FOXO1+ ARMS are reflected in differences in cells of origin, elevated numbers of molecular defined tumor-propagating cells (TPCs), and predisposition to metastasis. The feasibility of our approach is supported by our work in using zebrafish to model a wide range of human cancers, recent optimization of Crispr/CAS9 approaches to create patient-specific translocations using CRE/Lox, and our successful high-content imaging screening approach to identify FDA approved drugs with efficacy in curbing growth of other RMS subtypes. The rationale for our research is that there are few good experimental animal models that accurately mimic the underlying genetics of human ARMS, obviating our ability to define how specific oncogenic fusions drive cancer growth. This work is significant because it will uncover divergent cellular mechanisms that account for differences in the clinical manifestation of PAX3/7-FOXO1+ ARMS, identify new therapies to treat ARMS, and provide new modeling approaches for translocation+ cancers, all expressed goals outlined in PA-16-251 supported by the Cancer Moonshot Initiative. Aim 1 will characterize differences in PAX3/7-FOXO1-induced ARMS using innovative zebrafish models, testing our hypothesis that fusion+ ARMS have inherent differences in proliferation and cell(s)-of-origin. Aim 2 will assess PAX3/7-FRKH for differential effects on modulating metastasis and tumor propagating potential, testing our hypothesis that PAX3-FOXO1+ ARMS do worse clinically because they have elevated TPC numbers and metastatic capacity. Aim 3 will use an innovative high-content imaging screen to identify FDA-approved drugs that kill TPCs and suppress growth of human ARMS. With respect to outcomes, our research will develop much-needed precision animals models of ARMS and identify key differences in PAX3/7-FOXO1+ ARMS including likely differences in cell-of-origin, TPCs, and metastatic capacity, providing explanation of why PAX3-FOXO1+ ARMS do worse clinically. Our work will also identify novel therapies to kill TPCs in human patient derived xenografts (PDX). This work is expected to have a positive translational impact by demonstrating the pre-clinical efficacy of targeting TPCs in human ARMS and identifying new therapies for the treatment of this devastating cancer.

项目摘要（30行）牙槽横纹肌肉瘤（ARM）是一种常见和侵略性的肌肉癌，影响了数百种每年在美国的儿童。手臂是病原体，具有致癌染色体易位在PAX基因和叉头转录因子（FOXO1）之间。但是，PAX3/7-的途径 FOXO1转录因子调节，原始肿瘤细胞以及出现的治疗脆弱性武器细胞仍然不清楚，这主要是由于缺乏精确概括相同的精确动物模型在人武器中发现的易位融合事件。我们工作的长期目标是揭露治疗相关的途径，驱动武器生长。该应用程序的总体目的是开发斑马鱼识别可以在临床上利用的治疗漏洞的武器模型。我们的中心假设是 PAX3-FOXO1+手臂中较差的生存结果反映在原始细胞中的差异，升高分子定义的肿瘤传播细胞（TPC）的数量和转移的易感性。可行性我们的方法得到了我们在使用斑马鱼对广泛的人类癌症建模的工作的支持，最近优化CRISPR/CAS9方法使用CRE/LOX创建特定于患者的易位，我们成功的高含量成像筛选方法，以识别FDA批准的药物具有疗效其他RMS亚型的增长。我们研究的基本原理是很少有好的实验动物准确模仿人类手臂的基本遗传学的模型，从而避免了我们定义的能力特定的致癌融合驱动癌症的生长。这项工作很重要，因为它会发现不同的细胞机制解释了PAX3/7-FOXO1+ ARM的临床表现差异的差异，确定治疗武器的新疗法，并为易位+癌症提供新的建模方法在PA-16-251中概述了癌症月球倡议支持的目标。 AIM 1将表征使用创新的斑马鱼模型，PAX3/7-FOXO1诱导的手臂的差异，检验了我们的假设融合+手臂在增殖和细胞 - 原始素中具有固有的差异。 AIM 2将评估PAX3/7-FRKH 对于调节转移和肿瘤传播潜力的差异影响，我们检验了我们的假设 PAX3-FOXO1+手臂在临床上的情况更糟，因为它们的TPC数量升高和转移能力。 AIM 3将使用创新的高含量成像屏幕来识别FDA批准的药物，以杀死TPC和抑制人类武器的成长。关于结果，我们的研究将发展出急需的精度动物的武器模型，并确定PAX3/7-FOXO1+手臂的关键差异，包括可能的差异 Or-Of-Of-Of-of-of-of-of-of-tpc和转移能力，提供了为什么pax3-foxo1+手臂更糟的解释临床。我们的工作还将确定在人类衍生异种移植物（PDX）中杀死TPC的新型疗法。预计这项工作将通过证明临床前的疗效产生积极的翻译影响针对人类手臂中的TPC并确定用于治疗这种毁灭性癌症的新疗法。