High-throughput screening identifies the activity of histone deacetylase inhibitors in patient-derived models of soft tissue sarcoma
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Updated: Jan 6, 2026
Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Molly R Danks1, Piotr J Manasterski1, Henry Beetham1
1Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
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 IC50 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; ZIPmax: 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 mm3, doxorubicin 78.0 ± 35.2 mm3, quisinostat 84.3 ± 13.1 mm3, and combination 49.2 ± 10.2 mm3). 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.
Insights
Histone deacetylase (HDAC) inhibitors, like quisinostat, show promise for treating undifferentiated pleomorphic sarcoma (UPS). Quisinostat demonstrated significant tumor reduction and synergistic effects with doxorubicin in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Undifferentiated pleomorphic sarcoma (UPS) is an aggressive soft tissue sarcoma with limited therapeutic options and poor prognosis.
- UPS tumors have complex karyotypes, lack targetable mutations, and show low response rates to standard doxorubicin therapy.
- Phenotypic drug screening offers a strategy to identify novel therapeutic targets for UPS.
Purpose of the Study:
- To identify novel therapeutic agents for UPS through phenotypic drug screening.
- To evaluate the efficacy of histone deacetylase (HDAC) inhibitors, particularly quisinostat, as a potential treatment for UPS.
- To assess the synergistic effect of quisinostat in combination with doxorubicin.
Main Methods:
- Screening of FDA-approved compounds and a custom HDAC inhibitor library using patient-derived UPS cell lines.
- Characterization of hit compounds through apoptosis assays and in vivo xenograft studies.
- Evaluation of gene expression and western blot analyses for activity biomarkers and combination assays with doxorubicin.
Main Results:
- HDAC inhibitors, including quisinostat, exhibited potent activity with low IC50 values (14.8-26.89 nM) in UPS cell lines.
- Quisinostat demonstrated synergy with doxorubicin, enhancing apoptotic cell death in vitro and significantly reducing tumor volume in vivo.
- Quisinostat also showed potent activity in leiomyosarcoma (LMS) cell lines, another type of complex karyotype soft tissue sarcoma.
Conclusions:
- Quisinostat exhibits significant preclinical activity against UPS and LMS.
- Quisinostat demonstrates synergistic efficacy when combined with doxorubicin, a standard-of-care chemotherapy.
- HDAC inhibitors represent a promising therapeutic strategy for patients with UPS and potentially other complex karyotype sarcomas.
