Targeting EWS-ATF1 in CCSST

CCSST 中针对 EWS-ATF1

• 批准号: 9372101
• 负责人: Xiangshu Xiao
• 金额: $ 20.1万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372101
• 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.

该申请旨在开发一种治疗软组织透明细胞肉瘤（CCSST）的新型靶向治疗方法。 CCSST是一种罕见但侵袭性的软组织肉瘤，通常发生在下肢， 青少年和年轻人的肌腱和腱膜。转移癌的5年生存率只有20%， 疾病目前的治疗选择是进行广泛的局部手术切除或截肢， 以去除所有癌细胞。然而，在转移性病例中，完全去除癌细胞变得困难。 全身辅助治疗是控制该病的关键。不幸的是，这种疾病 由于其对当前化疗的不敏感性而臭名昭著，强调了开发新的 治疗CCSST。CCSST的特点是平衡的t（12;22）（q13;q12） 染色体易位，这导致尤文氏肉瘤基因EWS与激活的 转录因子1（ATF 1），得到癌基因EWS-ATF 1。ATF 1是cAMP反应性 元件结合蛋白（CREB）家族转录因子。EWS-ATF 1是组成性激活的， 通常由CREB/ATF 1控制的靶基因的表达。临床前研究表明， CCSST癌细胞依赖于EWS-ATF 1生存，这表明EWS-ATF 1是一种强大的免疫抑制剂。 旨在开发CCSST新疗法。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/ATF 1介导的基因转录。666-15在体内耐受良好。这些 初步结果表明，666-15完全适合于CCSST的潜在靶向治疗。到 为了验证这一假设，我们提出了两个具体的目的：1）评估666-15是否抑制EWS-ATF 1和EWS-1， 2）研究666-15是否具有抗CCSST活性。 实现这些目标可能为CCSST提供新的靶向治疗。