Pathogenic mechanisms of alveolar rhabdomyosarcoma

腺泡状横纹肌肉瘤的发病机制

• 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
• 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

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（由申请人提供）：儿科癌症是肿瘤学研究不足的领域。绝大多数癌症研究致力于了解成人恶性肿瘤，如乳腺癌、结肠癌、肺癌和皮肤癌。然而，儿科癌症最常见于不同的组织，如脑，骨和血液。这种发育组织的生物学景观被认为赋予了对致癌损伤的独特易感性，但我们对这种现象的分子基础的理解仍处于起步阶段。本申请的重点是一种与几种骨和软组织肿瘤（BSTT）病因有关的新型药物，BSTT是一类优先针对儿童和青少年的肿瘤。TRE 17易位发生在两种不同的BSTT中，囊性骨囊肿（ABC）和结节性筋膜炎（NF），导致其高水平表达。我们对一组广泛的原发性人类肿瘤的筛选进一步揭示了高表达，特别是在高百分比的腺泡状横纹肌肉瘤（ARMS）病例中。横纹肌肉瘤是最常见的小儿软组织肉瘤;各种亚型中，ARMS预后最差。 我的研究旨在阐明TRE 17的致病机制。我们最近的工作集中在其功能的背景下，ABC显示，它的功能细胞自主地促进肿瘤细胞增殖/存活，但也调节肿瘤微环境诱导多种细胞因子，趋化因子和生长因子的产生，在严格依赖于其USP活性的方式。我们进一步确定了NF？B和STAT 3是ABC发病机制中TRE 17的关键效应物。这两种转录因子在癌症中广泛失调，通常是协调的，其中它们发挥多效作用以促进肿瘤生长和转移的多个方面。 我们假设TRE 17在ARMS发病机制中起关键作用，NF B和STAT 3起关键效应物的作用。该建议将确定体外和体内对这三个因素的要求。体外分析将评估它们在细胞增殖、存活和细胞因子/生长因子产生中的作用，并将包括检查它们在癌细胞干细胞（CSC）亚群中的作用，据报道，CSC亚群依赖于NF？其他癌症中的B和STAT 3。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ARMS的治疗干预提供三个新的靶点。值得注意的是，NF？B和STAT 3通路已经被开发用于其他癌症和免疫疾病。此外，TRE 17特异性USP抑制剂不仅可以作为ARMS的有效治疗剂，还可以作为由TRE 17过表达驱动的其他BSTT的有效治疗剂。USP抑制剂特别有吸引力，因为TRE 17表现出这种有限的表达，使副作用的可能性最小化。