Targeting EWS-ATF1 Fusion in Clear Cell Sarcoma of Soft Tissue

靶向软组织透明细胞肉瘤中的 EWS-ATF1 融合

• 批准号: 10533381
• 负责人: Bingbing Li
• 金额: $ 43.83万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533381
• 关键词: Adjuvant Therapy; Adolescent and Young Adult; Amputation; Automobile Driving; Biochemical; Biological; Biological Assay; Cells; Chimeric Proteins; Chromosomal translocation; Chronic Myeloid Leukemia; Clear Cell Sarcoma; Combined Modality Therapy; Complex; Cyclic AMP-Responsive DNA-Binding Protein; Development; Diagnostic; Disease; Ewings sarcoma; Excision; Exhibits; Genes; Genetic Transcription; Genomics; Goals; In Vitro; Lower Extremity; Mediating; Molecular; Oncogenes; Operative Surgical Procedures; Patients; Pharmaceutical Chemistry; Phosphorylation; Protein Family; Protein-Arginine N-Methyltransferase; RNA-Binding Protein EWS; Rare Diseases; Research; Role; Safety; Soft tissue sarcoma; Survival Rate; Tendon structure; Testing; Tissue Model; Tissue Survival; Transcription Coactivator; Transcriptional Activation; activating transcription factor 1; aponeurosis; bcr-abl Fusion Proteins; cancer cell; chemical genetics; chemotherapy; disorder control; genetic approach; in vitro activity; in vivo; inhibitor; innovation; member; new therapeutic target; novel drug combination; novel therapeutics; preclinical study; protein arginine methyltransferase 2; small molecule; small molecule inhibitor; targeted treatment; therapeutic target; transcription factor; treatment strategy; tumor

PROJECT SUMMARY/ABSTRACT The goals of this application are to develop novel targeted therapies for clear cell sarcoma of soft tissue (CCSST) and understand their mechanism of action. CCSST is a rare and aggressive soft tissue sarcoma that typically develops in the lower extremity close to tendons and aponeuroses of adolescents and young adults. It is an orphan disease presently with no cure. The 5-year survival rate is only 20% for metastatic cases. The current treatment option is to perform wide local surgical resection or amputation attempting to remove all the cancer cells. However, in metastatic cases, complete removal of cancer cells becomes impossible and systemic adjuvant therapy is the key to control this disease. Unfortunately, this disease is notorious for its insensitivity to existing chemotherapies, underscoring an urgent need for developing novel targeted therapies for CCSST. The hallmark of CCSST is characterized by a balanced t(12;22) (q13;q12) chromosomal translocation, which results in a fusion of the Ewing's sarcoma gene EWSR1 (EWS RNA-bind protein 1) with activating transcription factor 1 (ATF1) to generate an oncogene EWS-ATF1. ATF1 is a member of the cAMP- responsive element binding protein (CREB) family transcription factor. EWS-ATF1 is constitutively active to drive the expression of target genes that are normally regulated by CREB/ATF1. In addition to ATF1, EWS- CREB fusion has also been detected in CCSST patients, further supporting a critical role of CREB/ATF1's transcription activity in driving the development of CCSST. In vitro and in vivo studies in various CCSST models have convincingly shown that CCSST cells depend on the EWS-ATF1-mediated gene transcription activity for continued survival. These results suggest that targeting EWS-ATF1 is a powerful and promising approach to develop novel targeted therapeutics for CCSST. As a transcription factor, EWS-ATF1 has been a challenging target for developing small molecule inhibitors. In addition, the mechanisms by which EWS-ATF1 activates gene transcription are not well-understood. We recently developed a small molecule called 666-15 as the first potent inhibitor of CREB/ATF1-mediated gene transcription. 666-15 is well-tolerated in vivo. In this application, we will investigate the activity of 666-15 in various CCSST models and its mechanism of action (Aim 1). We will further study how EWS-ATF1 activates gene transcription (Aim 2). In Aim 3, we will identify combination treatment strategies for CCSST.

项目总结/摘要 本申请的目的是为软组织透明细胞肉瘤开发新的靶向治疗方法 （CCSST）并了解其作用机制。CCSST是一种罕见的侵袭性软组织肉瘤， 通常发生在青少年和年轻人的下肢靠近肌腱和腱膜处。它 是一种目前无法治愈的孤儿病转移性病例的5年生存率仅为20%。的 目前的治疗选择是进行广泛的局部手术切除或截肢，试图去除所有的 癌细胞然而，在转移性病例中，完全去除癌细胞变得不可能， 全身辅助治疗是控制该病的关键。不幸的是，这种疾病因其 对现有化疗不敏感，强调迫切需要开发新的靶向治疗 对于CCSST。CCSST的特点是染色体t（12;22）（q13;q12）平衡 易位，导致尤文肉瘤基因EWSR 1（EWS RNA结合蛋白1）与 激活转录因子1（ATF 1）以产生致癌基因EWS-ATF 1。ATF 1是cAMP的成员。 反应元件结合蛋白（CREB）家族转录因子。EWS-ATF 1具有组成型活性， 驱动通常由CREB/ATF 1调节的靶基因的表达。除了ATF 1，EWS- 在CCSST患者中也检测到CREB融合，进一步支持CREB/ATF 1的关键作用 转录活性驱动CCSST的发育。各种CCSST的体外和体内研究 模型令人信服地表明，CCSST细胞依赖于EWS-ATF 1介导的基因转录， 为了继续生存。这些结果表明，靶向EWS-ATF 1是一种强大而有前途的方法， 方法开发新的CCSST靶向治疗。作为一种转录因子，EWS-ATF 1已经成为一种重要的转录因子。 开发小分子抑制剂的挑战性目标。此外，EWS-ATF 1的机制 激活基因转录的机制尚不清楚。我们最近开发了一种名为666-15的小分子， CREB/ATF 1介导的基因转录的第一个有效抑制剂。666-15在体内耐受良好。在这 应用，我们将研究666-15在各种CCSST模型中的活性及其作用机制 (Aim 1）。我们将进一步研究EWS-ATF 1如何激活基因转录（Aim 2）。在目标3中，我们将确定 CCSST的联合治疗策略。