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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该申请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）并了解其作用机制。 CCSST 是一种罕见且具有侵袭性的软组织肉瘤，通常发生在青少年和年轻人的下肢，靠近肌腱和腱膜。它是一种孤儿病，目前无法治愈。转移病例的5年生存率仅为20%。这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，在转移病例中，完全清除癌细胞是不可能的，并且全身辅助治疗是控制本病的关键。不幸的是，这种疾病因其严重性而臭名昭著。对现有化疗不敏感，强调迫切需要开发新型靶向疗法对于 CCSST。 CCSST 的标志是平衡的 t(12;22) (q13;q12) 染色体易位，导致尤文氏肉瘤基因 EWSR1（EWS RNA 结合蛋白 1）与激活转录因子 1 (ATF1) 以产生癌基因 EWS-ATF1。 ATF1 是 cAMP 的成员反应元件结合蛋白（CREB）家族转录因子。 EWS-ATF1 具有组成型活性驱动通常由 CREB/ATF1 调节的靶基因的表达。除了 ATF1 之外，EWS- CREB 融合也在 CCSST 患者中检测到，进一步支持 CREB/ATF1 的关键作用转录活性驱动 CCSST 的发展。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，靶向 EWS-ATF1 是一种强大且有前途的方法。开发针对 CCSST 的新型靶向疗法的方法。作为转录因子，EWS-ATF1 已成为开发小分子抑制剂的挑战性目标。此外，EWS-ATF1 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/ATF1 介导的基因转录的第一个有效抑制剂。 666-15 在体内具有良好的耐受性。在这个应用后，我们将研究666-15在各种CCSST模型中的活性及其作用机制（目标 1）。我们将进一步研究EWS-ATF1如何激活基因转录（目标2）。在目标 3 中，我们将确定 CCSST 的联合治疗策略。