Therapeutic Potential of Bromodomain and Extra-Terminal Domain Inhibitors for Synovial Sarcoma Cells.

Synovial sarcoma (SS), a rare subtype of soft-tissue sarcoma distinguished by expression of the fusion gene SS18-SSX, predominantly affects the extremities of young patients. Existing anticancer drugs have limited efficacy against this malignancy, necessitating the development of innovative therapeutic approaches. Given the established role of SS18-SSX in epigenetic regulation, we focused on bromodomain and extra-terminal domain protein (BET) inhibitors and epigenetic agents. Our investigation of the BET inhibitor ABBV-075 revealed its pronounced antitumor effects, inducing G1-phase cell-cycle arrest and apoptosis, in four SS cell lines. Notably, BET inhibitors exhibited regulatory control over crucial cell-cycle regulators, such as MYC, p21, CDK4, and CDK6. Additionally, RNA sequencing findings across the four cell lines revealed the significance of fluctuating BCL2 family protein expression during apoptotic induction. Notably, variations in the expression ratio of the anti-apoptotic factor BCLxL and the pro-apoptotic factor BIM may underlie susceptibility to ABBV-075. Additionally, knockdown of SS18-SSX, which upregulates BCL2, reduced the sensitivity to ABBV-075. These findings suggest the potential utility of BET inhibitors targeting the SS18-SSX-regulated intrinsic apoptotic pathway as a promising therapeutic strategy for SS.

Targeting the Clear Cell Sarcoma Oncogenic Driver Fusion Gene EWSR1::ATF1 by HDAC Inhibition.

Clear cell sarcoma (CCS), a rare but extremely aggressive malignancy with no effective therapy, is characterized by the expression of the oncogenic driver fusion gene EWSR1::ATF1. In this study, we performed a high-throughput drug screening, finding that the histone deacetylase inhibitor vorinostat exerted an antiproliferation effect with the reduced expression of EWSR1::ATF1. We expected the reduced expression of EWSR1::ATF1 to be due to the alteration of chromatin accessibility; however, assay for transposase-accessible chromatin using sequencing and a cleavage under targets and release using nuclease assay revealed that chromatin structure was only slightly altered, despite histone deacetylation at the EWSR1::ATF1 promoter region. Alternatively, we found that vorinostat treatment reduced the level of BRD4, a member of the bromodomain and extraterminal motif protein family, at the EWSR1::ATF1 promoter region. Furthermore, the BRD4 inhibitor JQ1 downregulated EWSR1::ATF1 according to Western blotting and qPCR analyses. In addition, motif analysis revealed that vorinostat treatment suppressed the transcriptional factor SOX10, which directly regulates EWSR1::ATF1 expression and is involved in CCS proliferation. Importantly, we demonstrate that a combination therapy of vorinostat and JQ1 synergistically enhances antiproliferation effect and EWSR1::ATF1 suppression. These results highlight a novel fusion gene suppression mechanism achieved using epigenetic modification agents and provide a potential therapeutic target for fusion gene-related tumors. Significance: This study reveals the epigenetic and transcriptional suppression mechanism of the fusion oncogene EWSR1::ATF1 in clear cell sarcoma by histone deacetylase inhibitor treatment as well as identifying SOX10 as a transcription factor that regulates EWSR1::ATF1 expression.

Tocilizumab Controls Paraneoplastic Inflammatory Syndrome but Does Not Suppress Tumor Growth of Angiomatoid Fibrous Histiocytoma.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that rarely metastasizes but lacks effective systemic therapy once it propagates. In some reports, high interleukin-6 (IL-6) production promotes tumor growth by autocrine stimulation and tocilizumab, an IL-6 receptor antagonist, can control AFH growth. Here, we present a case report on a patient with local recurrence and distant lymph node metastasis of AFH treated with tocilizumab. As a result, the inhibition of the IL-6 signaling pathway controlled paraneoplastic inflammatory syndrome (PIS); however, the local recurrent tumor progressed. This case implied that IL-6 is not necessarily the cause of tumor growth in AFH. Therefore, physicians should bear in mind that watchful observation is needed whether tocilizumab can control tumor progression despite the amelioration of PIS associated with the attenuated effect of IL-6 on AFH.

Prognostic factors and skeletal-related events in patients with bone metastasis from gastric cancer.

The number of studies on bone metastasis (BM) from gastric cancer (GC) is currently limited. Therefore, the aim of the present study was to investigate the characteristics, skeletal-related events (SREs) and prognosis of GC in patients with BMs. Data from 60 patients with BMs from GC were retrospectively retrieved and patient-, tumor- and BM-related characteristics were analyzed. Kaplan-Meier survival curves were analyzed using the univariate log-rank test. Multivariate analyses were conducted using the Cox proportional hazards model. The median patient age was 63.5 years (range, 26-83 years). Visceral or brain metastases were observed at BM diagnosis in 61.7% of the patients. Multiple BMs were detected in 83.3% and SREs occurred in 76.7% of the patients. The median overall survival (OS) after BM diagnosis and SRE occurrence was 9 months (range, 0-43 months) and 5 months (range, 0-36 months), respectively. On multivariate analysis, poor Eastern Cooperative Oncology Group performance status (P=0.030), the administration of chemotherapy prior to BM diagnosis (P<0.001) and no chemotherapy after BM diagnosis (P=0.002) were significant prognostic factors for unfavorable OS, whereas the non-use of bone-modifying agents (BMAs) was the only independent prognostic factor for poor SRE-free survival (SRS; P=0.022). Among patients without SREs at BM diagnosis, the median SRS duration was 7 months (range, 0-43 months). In conclusion, chemotherapy may confer a survival benefit in GC patients with BMs. In addition, the prognosis for GC patients with BMs presenting with SREs is poor, but treatment with BMAs may prevent or delay the development of SREs.