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.