Pathogenic mechanisms of alveolar rhabdomyosarcoma

描述(由申请人提供)：儿童癌症是肿瘤学中研究不足的领域。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，儿童癌症最常见的是发生在不同的组织，如脑、骨和血液。这种发育中的组织的生物景观被认为赋予了对致癌性侮辱的明显敏感性，但我们对这种现象的分子基础的理解仍处于初级阶段。这项应用集中在一种与几种骨和软组织肿瘤(BSTT)的病因学有关的新药物上，BSTT是一类优先针对儿童和青少年的肿瘤。TRE17易位发生在两种不同的BSTT中，即动脉瘤性骨囊肿(ABC)和结节性筋膜炎(NF)，导致其高水平表达。我们对广泛的原发人类肿瘤的筛查进一步显示高表达，特别是在高比例的肺泡型横纹肌肉瘤(ARMS)病例中。横纹肌肉瘤是最常见的儿童软组织肉瘤；在各种亚型中，ARM预后最差。本研究旨在阐明TRE17的致病机制。我们最近在ABC背景下对其功能的研究表明，它的功能是细胞自主的，促进肿瘤细胞的增殖/存活，但也通过诱导多种细胞因子、趋化因子和生长因子的产生来调节肿瘤微环境，其方式严格依赖于其USP活性。我们进一步确定了NFB和STAT3是TRE17在ABC发病机制中的关键效应因子。这两种转录因子在癌症中都是普遍失调的，通常是协调的，它们发挥多向性的作用，促进肿瘤生长和转移的多个方面。我们假设TRE17在ARM的发病机制中起关键作用，而NFB和STAT3是关键的效应因子。这一建议将决定这三个因素在体外和体内的需求。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RLE，并将包括检测它们在癌细胞干细胞(CSC)亚群中的作用，据报道，CSC亚群在其他癌症中依赖于核因子？B和STAT3。体内研究将检验它们在肿瘤形成、肿瘤维持和转移中的作用。如果成功，这些研究将为武器治疗干预提供三个新的目标。值得注意的是，针对NF？B和STAT3途径的抑制剂已经在积极开发，用于治疗其他癌症和免疫疾病。此外，TRE17特异性的USP抑制剂可能不仅对ARM，而且对由TRE17过表达驱动的其他BSTT具有有效的治疗作用。USP抑制剂特别有吸引力，因为TRE17表现出如此有限的表达，将副作用的可能性降至最低。

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.