Abstract
BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a rare and aggressive soft tissue sarcoma with limited treatment options and a poor prognosis. As a complex karyotype tumor, UPS lacks recurrent targetable mutations, and response rates to standard first-line doxorubicin therapy are low. Phenotypic drug screening offers an alternative approach to identify new therapeutic targets without requiring prior knowledge of molecular mechanisms. METHODS: A library of FDA-approved compounds and a custom histone deacetylase (HDAC) inhibitor library were screened using well-annotated patient-derived cell lines. Hit compounds were further characterized using apoptosis assays and in vivo xenograft studies. Biomarkers of activity were evaluated using gene expression and western blot analyses. Synergy with doxorubicin was evaluated in combination assays. RESULTS: HDAC inhibitors emerged as a promising therapeutic class, demonstrating low IC(50) values across cell lines (14.8-26.89 nM), with quisinostat taken forward for further evaluation. Gene expression changes in EPAS1, FOXO1, AMOT, and FOSL1 were observed as potential biomarkers of activity. Combination assays revealed synergy between quisinostat and doxorubicin (average ZIP score: 1.02-15.65; ZIP(max): 3.98-33.71), increasing apoptotic cell death in vitro. In vivo, quisinostat alone and in combination with doxorubicin significantly reduced the tumor volume (vehicle 160.0 ± 63.2 mm(3), doxorubicin 78.0 ± 35.2 mm(3), quisinostat 84.3 ± 13.1 mm(3), and combination 49.2 ± 10.2 mm(3)). Quisinostat also showed potent activity in leiomyosarcoma (LMS) cell lines (5.82-31.32 nM), which represent an additional complex karyotype soft tissue sarcoma. CONCLUSIONS: Quisinostat demonstrated strong preclinical activity and synergy with standard-of-care doxorubicin in models of UPS and LMS.