Project Summary Solitary fibrous tumor (SFT), historically also called hemangiopericytoma (HPC), is a soft-tissue sarcoma occurring in adults and infants. This nonhereditary cancer is a result of an environmental intrachromosomal gene fusion between NAB2 and STAT6 on chromosome 12, which fuses the activation domain of STAT6 with the repression domain of NAB2. Consequently, instead of NAB2 repressing early growth response (EGR-1) target genes, the fusion protein activates them leading to tumorigenesis. There are at least 6 distinct fusion variants that account for pathologic variation and tumor aggressiveness in SFTs. Anatomically, these blood vessel-derived tumors can occur anywhere; however, most occur within the meninges of the head. Intracranial SFTs have a high rate of local recurrence (65%), metastases (33%) and overall survival less than 10 years. Either surgery or radiation is the first line of treatment against this cancer, however for many this becomes challenging as the cancer can travel to inoperable areas or reoccur in locations already irradiated. Currently there is no approved chemotherapy regimen for SFTs. Anti-angiogenic drugs developed to treat other cancers have been used on SFTs with limited success. None of the chemotherapies enables complete remission, with the best response being a partial response or stable disease for several months. The average survival of patients on the current chemotherapies is 2 years. Using the CRISPR-based genome editing, we established SFT cell models which closely match the endogenous NAB2-STAT6 genetic characteristics. In addition, we prepared several primary SFT cell lines and a PDX animal model from resected patient tissue samples that faithfully recapitulates phenotypes of malignant SFTs. Using these SFT models, we performed a high-throughput assay, which identified the BET inhibitor Mivebresib as a promising candidate against SFTs. Here, we propose the following three aims: (a) perform comprehensive phenotypi