Pathogenic mechanisms of alveolar rhabdomyosarcoma

腺泡状横纹肌肉瘤的发病机制

基本信息

批准号：
8570230
负责人：
Margaret Mary Chou
金额：
$ 21.86万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8570230
关键词：
Accounting Adolescent Adult Adverse effects Alveolar Rhabdomyosarcoma Aneurysmal Bone Cysts Area Biological Biology Blood Bone Tissue Brain Carcinoma Cell Line Cell Proliferation Cell Survival Cell physiology Cells Child Childhood Childhood Soft Tissue Sarcoma Colon Combined Modality Therapy Connective and Soft Tissue Neoplasm Development Dominant-Negative Mutation Etiology Exhibits FOXO1A gene Fasciitis Foundations Future Gene Expression Profile Genes Goals Growth Factor Human Immune System Diseases Immunohistochemistry In Vitro Laboratories Lung Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Mediating Mediator of activation protein Microarray Analysis Molecular Molecular Profiling Monitor Mus Neoplasm Metastasis Neoplasms Nude Mice Oncogenic PAX3 gene PAX7 gene Pathogenesis Pathway interactions Patients Play Predisposition Production Prognostic Marker Proteins Recurrence Reporting Research Rhabdomyosarcoma Role STAT3 gene Sampling Skin Soft Tissue Neoplasms Solid Testing Therapeutic Agents Therapeutic Intervention Time Tissues Transcription Coactivator Translating Work Xenograft Model Xenograft procedure activating transcription factor angiogenesis anticancer research base bone cancer stem cell cancer type chemokine comparative cytokine human USP6 protein in vivo infancy inhibitor/antagonist insight malignant breast neoplasm mortality mouse model neoplastic cell new therapeutic target novel novel therapeutic intervention oncology outcome forecast overexpression prognostic promoter public health relevance research study sarcoma screening small hairpin RNA soft tissue transcription factor tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Pediatric cancers represent an understudied area in oncology. The great majority of cancer research is dedicated to understanding adult malignancies, such as cancers of the breast, colon, lung and skin. However, pediatric cancers most commonly arise in distinct tissues, such as brain, bone, and blood. The biological landscape of such developing tissues is believed to confer a distinct susceptibility to oncogenic insults, but our understanding of the molecular basis of this phenomenon is still in its infancy. This application focuses on a novel agent implicated in the etiology of several bone and soft tissue tumors (BSTTs), a class of tumors that preferentially targets children and adolescents. TRE17 translocation occurs in two distinct BSTTs, aneurysmal bone cyst (ABC) and nodular fasciitis (NF), leading to its high level expression. Our screening of a wide panel of primary human tumors further revealed high expression specifically in a high percentage of alveolar rhabdomyosarcoma (ARMS) cases. Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma; of the various subtypes, ARMS carries the worst prognosis. My research is aimed at elucidating the pathogenic mechanisms of TRE17. Our recent work focusing on its functions in the context of ABC revealed that it functions cell-autonomously to promote tumor cell proliferation/survival, but also regulates the tumor microenvironment by inducing the production of multiple cytokines, chemokines, and growth factors, in a manner strictly dependent on its USP activity. We further identified NF?B and STAT3 as key effectors of TRE17 in ABC pathogenesis. Both of these transcription factors are widely dysregulated in cancer, often coordinately, where they function pleiotropically to promote multiple aspects of tumor growth and metastasis. We hypothesize that TRE17 plays a key role in ARMS pathogenesis, and that NF¿B and STAT3 function as critical effectors. This proposal will determine the requirement of these three factors both in vitro and in vivo. In vitro analyses will assess their rle in cell proliferation, survival, and cytokine/growth factor production, and will include examining their role within the cancer cell stem (CSC) subpopulation, which has been reported to be dependent on NF?B and STAT3 in other cancers. In vivo studies will examine their role in tumor formation, tumor maintenance, and metastasis. If successful, these studies would provide three novel targets for therapeutic intervention in ARMS. Notably, inhibitors for NF?B and STAT3 pathways are already being avidly developed for other cancers and immune disorders. Furthermore, TRE17-specific USP inhibitors might function as effective therapeutic agents for not only ARMS, but also other BSTTs driven by TRE17 overexpression. USP inhibitors are particularly appealing since TRE17 exhibits such limited expression, minimizing the likelihood of side effects.

描述（由适用提供）：小儿癌症代表肿瘤学中的一个理解区域。绝大多数癌症研究致力于理解成人恶性肿瘤，例如乳腺癌，结肠，肺和皮肤的癌症。但是，小儿癌最常见于大脑，骨骼和血液等不同组织中。据信这种发展组织的生物学景观可以使人们对致癌感染有着明显的敏感性，但是我们对这种现象的分子基础的理解仍处于起步阶段。该应用的重点是在几个骨骼和软组织肿瘤（BSTT）的病因中实现的新药物，这是一类优先针对儿童和青少年的肿瘤。 TRE17易位发生在两个不同的BSTT中，动脉瘤骨囊肿（ABC）和结节性筋膜炎（NF），导致其高水平的表达。我们对一系列原发性人类肿瘤的筛查进一步揭示了高表达，特别是在肺泡横纹肌肉瘤（ARM）病例中。横纹肌肉瘤是最常见的小儿软组织肉瘤。在各种亚型中，武器具有最差的预后。我的研究旨在阐明TRE17的致病机制。我们最近关注其在ABC背景下的功能的工作表明，它的功能 - 自治性以促进肿瘤细胞增殖/生存，但也通过严格依赖其USP活性的方式来调节肿瘤微环境。我们进一步将NF？B和STAT3确定为TRE17在ABC发病机理中的关键影响。这两种转录因子在癌症中均广泛失调，通常是协调的，在这些因素上，它们在癌症上起作用以促进肿瘤生长和转移的多个方面。我们假设TRE17在武器发病机理中起关键作用，而NF¿B和STAT3起着关键作用。该建议将确定体外和体内这三个因素的要求。体外分析将评估其在细胞增殖，存活和细胞因子/生长因子产生中的RLE，并包括检查其在癌细胞茎（CSC）亚群中的作用，据报道，这些作用依赖于其他癌症中的NF？B和Stat3。体内研究将检查它们在肿瘤形成，肿瘤维持和转移中的作用。如果成功，这些研究将为武器热干预提供三个新的目标。值得注意的是，NF？B和STAT3途径的抑制剂已经为其他癌症和免疫疾病开发。此外，TRE17特异性USP抑制剂可能不仅可以作为臂的有效治疗剂，而且还可以作为TRE17过表达驱动的其他BSTT。 USP抑制剂特别有吸引力，因为TRE17表现出如此有限的表达，从而最大程度地减少了副作用的可能性。