Abstract 84P
Background
Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm driven by the NAB2-STAT6 fusion gene. While surgery and radiation remain the mainstay treatments, chemotherapeutic options for advanced or recurrent SFT are limited. Bromodomain and extra-terminal protein inhibitors (BETis) have shown promising therapeutic potential across various cancers, including certain sarcoma subtypes. Through high-throughput screening, we identified Mivebresib as an active BETi in cells harboring the NAB2-STAT6 fusion, underscoring its potential as a targeted therapy for this challenging tumor.
Methods
In SFT cell lines (INT-SFT, IEC139) cell viability and synergy were assessed by MTS assay, apoptosis by flow cytometry, and protein expression by Western blot. Nude mice with SFT patient-derived xenografts were treated with mivebresib (1 mg/kg) and tumor volume monitored. RNA-seq was performed on Illumina NovaSeq X.
Results
Among seven BETis tested in SFT cells, Mivebresib and BMS-986158 exhibited the lowest IC50 values (INT-SFT: 10.8 nM and 6.23 nM; IEC139: 12.5 nM and 28.8 nM) and, in contrast to other BETis, induced apoptosis at 50 nM (INT-SFT: 32% and 45.9%; IEC139: 27.5% and 34.3%). Both drugs caused cell cycle arrest in the G1 phase (up to 1.8-fold increase), with upregulation of the DNA damage regulator p21 and downregulation of cyclin D1. Marked increases in the apoptotic marker cleaved PARP-1 and the double-strand break marker γ-H2AX (up to 49.1-fold) were also observed. Combining BETis with PARPi rucaparib or ATRi berzosertib showed synergistic effects, enhancing apoptotic responses and DNA damage accumulation. RNA-seq analysis revealed that BETi treatment downregulated gene sets related to interferon signaling and epithelial-mesenchymal transition. In vivo, Mivebresib reduced tumor growth in SFT PDX models by 65.2% on day 24 compared to vehicle-treated controls.
Conclusions
Mivebresib and BMS-986158 are potent BETis with significant anti-tumor activity in SFT, inducing apoptosis, cell cycle arrest, and DNA damage. The combination of BETis with PARPi or ATRi further enhanced therapeutic effects, highlighting their synergistic potential. In vivo, Mivebresib markedly reduced tumor growth in SFT PDX models, supporting its potential as a targeted therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Institute of Health (NIH): Research project (R01) grant.
Disclosure
D. Da Silva Moura: Financial Interests, Personal, Invited Speaker: Tecnofarma; Financial Interests, Personal, Stocks/Shares: Sarcoma Research Solutions; Other, Personal, Other, Funding related with flight and accommodation at scientific meetings.: PharmaMar. J. Martin-Broto: Financial Interests, Personal, Expert Testimony, Honoraria: Lilly, PharmaMar, Eisai, Bayer, Roche, Boehringer Ingelheim, Amgen; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Personal, Advisory Board, Speaker: Tecnofarma, Asofarma; Financial Interests, Personal, Other, Profits: Sarcoma Research Solutions SL; Financial Interests, Institutional, Invited Speaker: PharmaMar, Eisai, Novartis, IMMIX Biopharma, Lixte, Karyopharm, Bayer, Celgene, Pfizer, BMS, Blueprint, Deciphera, NEKTAR, FORMA, Amgen, Daiichi Sankyo, Lilly, AROG, Adaptimmune, GSK, Ran Therapeutics, INHIBRX, Ayala Pharmaceuticals, Philogen, Cebiotex, PTC Therapeutics, Inc. and SpringWorks therapeutics. All other authors have declared no conflicts of interest.