Tuesday, February 7, 2023
2/7/2023
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.
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