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.

项目摘要/摘要 该应用的目标是开发针对软组织透明细胞肉瘤的新型靶向疗法 （CCSST）并了解其作用机理。 CCSST是一种罕见且具有侵略性的软组织肉瘤 通常在下肢发展，靠近青少年和年轻人的肌腱和蛋白尿。它 目前是一种孤儿病，无法治愈。转移性病例的5年生存率仅为20％。这 当前的治疗选择是进行局部局部手术切除或截肢试图去除所有 癌细胞。但是，在转移性情况下，完全去除癌细胞是不可能的，并且 全身辅助治疗是控制这种疾病的关键。不幸的是，这种疾病因其臭名昭著 对现有化学疗法的不敏感，强调迫切需要开发新的目标疗法 对于CCSST。 CCSST的标志的特征是平衡t（12; 22）（Q13; Q12）染色体 易位，导致Ewing的肉瘤基因EWSR1（EWS RNA结合蛋白1）与 激活转录因子1（ATF1）生成癌基因EWS-ATF1。 ATF1是营地的成员 响应元件结合蛋白（CREB）家族转录因子。 EWS-ATF1具有组成性活动 驱动通常由CREB/ATF1调节的靶基因的表达。除了ATF1，EWS- 在CCSST患者中也检测到CREB融合，进一步支持CREB/ATF1的关键作用 驱动CCSST开发的转录活性。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-ATF1介导的基因转录 持续生存的活动。这些结果表明，针对EWS-ATF1是一个有力而有前途的 开发新颖的CCSST靶向疗法的方法。作为转录因子，EWS-ATF1一直是 发展小分子抑制剂的挑战靶标。另外，EWS-ATF1的机制 激活基因转录并不理解。我们最近开发了一个称为666-15的小分子 CREB/ATF1介导的基因转录的第一个有效抑制剂。 666-15在体内耐受性良好。在这个 应用，我们将研究各种CCSST模型中666-15的活动及其作用机理 （目标1）。我们将进一步研究EWS-ATF1如何激活基因转录（AIM 2）。在AIM 3中，我们将确定 CCSST的组合治疗策略。