Pathogenic mechanisms of alveolar rhabdomyosarcoma

描述（由申请人提供）：儿科癌症代表了肿瘤学中一个未被充分研究的领域。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，儿童癌症最常发生在不同的组织，如脑、骨和血液。这类发育组织的生物学特征被认为具有明显的致癌易感性，但我们对这一现象的分子基础的理解仍处于起步阶段。本研究的重点是一种涉及几种骨和软组织肿瘤（BSTTs）病因学的新型药物，BSTTs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，动脉瘤性骨囊肿（ABC）和结节性筋膜炎（NF），导致其高水平表达。我们对广泛的原发性人类肿瘤的筛选进一步揭示了高表达，特别是在高比例的肺泡横纹肌肉瘤（ARMS）病例中。横纹肌肉瘤是最常见的小儿软组织肉瘤；在各种亚型中，ARMS预后最差。我的研究旨在阐明TRE17的致病机制。我们最近的工作重点是其在ABC背景下的功能，揭示了它的细胞自主功能，促进肿瘤细胞增殖/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NF？B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普遍失调，通常是协调的，它们多效性地促进肿瘤生长和转移的多个方面。我们假设TRE17在ARMS发病机制中起关键作用，NF¿B和STAT3是关键效应物。本方案将确定这三种因素在体外和体内的需要量。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依赖于NF？B和STAT3在其他癌症中的表达。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ARMS的治疗干预提供三个新的靶点。值得注意的是NF？B和STAT3通路已经被热切地开发用于其他癌症和免疫疾病。此外，TRE17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TRE17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TRE17表现出如此有限的表达，最大限度地减少了副作用的可能性。

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.