New models and therapeutic approaches in alveolar rhabdomyosarcoma

肺泡横纹肌肉瘤的新模型和治疗方法

• 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
• 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

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） 腺泡状横纹肌肉瘤 (ARMS) 是一种常见的侵袭性肌肉癌症，影响数百名患者 每年都有孩子在美国。 ARMS 与致癌染色体易位具有特征性 PAX 基因和叉头转录因子 (FOXO1) 之间的关系。然而，PAX3/7- FOXO1 转录因子调节肿瘤细胞的起源以及出现的治疗脆弱性 ARMS 细胞仍不清楚，很大程度上是由于缺乏精确的动物模型来准确概括相同的细胞 在人类 ARMS 中发现的易位融合事件。我们工作的长期目标是发现治疗方法 推动 ARMS 增长的相关途径。该应用程序的总体目标是开发斑马鱼 ARMS 模型来识别可在临床上利用的治疗漏洞。我们的中心假设是 PAX3-FOXO1+ ARMS 中较差的生存结果反映在来源细胞的差异上，升高 分子定义的肿瘤增殖细胞（TPC）的数量以及转移倾向。可行性 我们的方法得到了我们使用斑马鱼模拟多种人类癌症的工作的支持，最近 优化 Crispr/CAS9 方法以使用 CRE/Lox 创建患者特异性易位，以及我们的 成功的高内涵成像筛选方法来识别 FDA 批准的药物，有效抑制 其他 RMS 亚型的增长。我们研究的理由是好的实验动物很少 准确模拟人类 ARMS 潜在遗传学的模型，使我们无法定义如何 特定的致癌融合会促进癌症的生长。这项工作意义重大，因为它将揭示不同的 解释 PAX3/7-FOXO1+ ARMS 临床表现差异的细胞机制， 确定治疗 ARMS 的新疗法，并为易位+癌症提供新的建模方法，所有 PA-16-251 中阐述了癌症登月计划支持的目标。目标 1 将表征 使用创新斑马鱼模型研究 PAX3/7-FOXO1 诱导的 ARMS 的差异，检验我们的假设 融合+ ARMS 在增殖和细胞来源方面具有固有的差异。目标 2 将评估 PAX3/7-FRKH 对于调节转移和肿瘤增殖潜力的不同作用，检验我们的假设 PAX3-FOXO1+ ARMS 的临床表现较差，因为它们的 TPC 数量和转移能力较高。 Aim 3 将使用创新的高内涵成像屏幕来识别 FDA 批准的杀死 TPC 的药物， 抑制人类手臂的生长。就结果而言，我们的研究将达到急需的精确度 ARMS 动物模型并确定 PAX3/7-FOXO1+ ARMS 的主要差异，包括可能的差异 细胞起源、TPC 和转移能力，解释了为什么 PAX3-FOXO1+ ARMS 表现更差 临床上。我们的工作还将确定杀死人类患者异种移植物 (PDX) 中 TPC 的新疗法。 这项工作预计将通过证明临床前疗效产生积极的转化影响 针对人类 ARMS 中的 TPC 并确定治疗这种毁灭性癌症的新疗法。