Targeting EWS-ATF1 in CCSST

CCSST 中针对 EWS-ATF1

• 批准号: 9527099
• 负责人: Xiangshu Xiao
• 金额: $ 16.75万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9527099
• 关键词: Adjuvant Therapy; Adolescent and Young Adult; Adult; Amputation; Biological Assay; Biology; Cell Line; Cells; Chimeric Proteins; Chromosomal translocation; Clear Cell Sarcoma; Complex; Cyclic AMP-Responsive DNA-Binding Protein; Diagnostic; Disease; Ewings sarcoma; Excision; Gene Fusion; Gene Targeting; Genes; Genetic Transcription; In Vitro; Lower Extremity; Mediating; Oncogenes; Operative Surgical Procedures; Pathogenesis; Patients; Pharmaceutical Chemistry; Plant Roots; Protein Family; Rare Diseases; Research; Series; Soft tissue sarcoma; Survival Rate; Tendon structure; Testing; Tissue Survival; activating transcription factor 1; bcr-abl Fusion Proteins; cancer cell; cell growth; chemotherapy; childhood sarcoma; design; disorder control; experimental study; in vivo; inhibitor/antagonist; member; new therapeutic target; novel; novel therapeutics; preclinical study; response; small molecule; small molecule inhibitor; targeted treatment; tool; transcription factor; tumor

This application is to develop a novel targeted therapy for clear cell sarcoma of soft tissue (CCSST). CCSST is a rare but aggressive soft tissue sarcoma that typically develops in the lower extremity close to tendons and aponeuroses of adolescents and young adults. The 5-year survival is only 20% for metastatic disease. 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 current chemotherapies, underscoring an urgent need for developing novel 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 EWS with activating transcription factor 1 (ATF1) to give 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 controlled by CREB/ATF1. Preclinical studies have shown that CCSST cancer cells are dependent on EWS-ATF1 for survival, suggesting that EWS-ATF1 is a powerful target to develop novel therapies for CCSST. We recently developed a small molecule called 666-15 as the first potent inhibitor CREB/ATF1-mediated gene transcription. 666-15 is well-tolerated in vivo. These preliminary results suggest that 666-15 is perfectly suited for a potential targeted therapy for CCSST. To test this hypothesis, we propose two specific aims: 1) To evaluate if 666-15 inhibits EWS-ATF1 and EWS- CREB-mediated gene transcription; 2) To investigate if 666-15 possesses anti-CCSST activity. Accomplishing these aims can potentially provide a novel targeted therapy for CCSST.

本研究旨在为软组织透明细胞肉瘤(CCSST)提供一种新的靶向治疗方法。 CCSST是一种罕见但侵袭性很强的软组织肉瘤，通常发生在 青少年和青壮年的肌腱和腱膜。转移瘤的5年生存率仅为20%。 疾病。目前的治疗选择是进行广泛的局部手术切除或尝试截肢。 来移除所有的癌细胞。然而，在转移性病例中，癌细胞完全移除成为 不可能的、系统的辅助治疗是控制本病的关键。不幸的是，这种疾病是 因对目前的化疗药物不敏感而臭名昭著，突显出开发新的 CCSST的治疗方法。CCSST的特点是t(12；22)(q13；q12)平衡 染色体易位，导致尤文肉瘤基因EWS与激活的融合 转录因子1(Atf1)，产生癌基因EWS-atf1。Atf1是夏令营的一员--响应 元件结合蛋白(CREB)家族转录因子。EWS-atf1在结构上是活跃的，可以驱动 通常由CREB/atf1调控的靶基因的表达。临床前研究表明， CCSST癌细胞的生存依赖于EWS-atf1，提示EWS-atf1是一种强大的 目标是为CCSST开发新的治疗方法。我们最近开发了一种名为666-15的小分子 第一个有效的抑制剂CREB/atf1介导的基因转录。666-15在体内耐受性良好。这些 初步结果表明，666-15非常适合于CCSST的潜在靶向治疗。至 为了验证这一假说，我们提出了两个具体的目标：1)评估666-15是否抑制EWS-atf1和EWS-ATF1 CREB介导的基因转录；2)研究666-15是否具有抗CCSST活性。 这些目标的实现可能为CCSST提供一种新的靶向治疗方法。