Innovative Breakthroughs for the Treatment of Advanced and Metastatic Synovial Sarcoma

Abstract

Synovial sarcoma (SyS) is a rare aggressive soft tissue sarcoma carrying the chromosomal translocation t(X;18), encoding the fusion transcript SS18::SSX. The fusion oncoprotein interacts with both BAF enhancer complexes and polycomb repressor complexes, resulting in genome-wide epigenetic perturbations and a unique altered genetic signature. Over 80% of the patients are initially diagnosed with localized disease and have a 5-year survival rate of 70–80%, but metastatic relapse occurs in 50% of the cases. Advanced, unresectable, or metastatic disease has a 5-year survival rate below 10%, representing a critical issue. This review summarizes the molecular mechanisms behind SyS and illustrates current treatments in front line, second line, and beyond settings. We analyze the use of immune check point inhibitors (ICI) in SyS that do not behave as an ICI-sensitive tumor, claiming the need for predictive genetic signatures and tumor immune microenvironment biomarkers. We highlight the clinical translation of innovative technologies, such as proteolysis targeting chimera (PROTAC) protein degraders or adoptive transfer of engineered immune cells. Adoptive cell transfer of engineered T-cell receptor cells targeting selected cancer/testis antigens has shown promising results against metastatic SyS in early clinical trials and further improvements are awaited from refinements involving immune cell engineering and tumor immune microenvironment enhancement.

Low NT5DC2 expression predicts favorable prognosis and suppresses soft tissue sarcoma progression via ECM-receptor interaction pathway

“…Despite extensive research efforts, the etiology of soft tissue sarcoma remains elusive and due to the limited efficacy of chemotherapy and radiotherapy in soft tissue sarcoma patients, surgery is still the main treatment [ 19 , 20 ]. Meanwhile, soft tissue sarcoma has high recurrence and lung metastasis rates, and patients with advanced-stage soft tissue sarcoma cannot tolerate surgery, chemotherapy or radiotherapy [ 21 , 22 ]. These challenges result in a poor prognosis in soft tissue sarcoma patients.…”

DNA-Dependent Protein Kinase Inhibitor Peposertib Potentiates the Cytotoxicity of Topoisomerase II Inhibitors in Synovial Sarcoma Models

“…The inadequacy of current treatment approaches is highlighted by the limited improvements in overall survival rates with existing therapies over the last decades [ 1 , 29 ]. Innovative approaches that exploit the unique molecular characteristics of synovial sarcoma, such as targeting SS18-SSX fusion gene-related pathways, epigenetic modifications, and immunomodulation, offer a compelling avenue for therapeutic innovation, but it remains elusive if these will demonstrate clinical benefit and result in regulatory approvals for this rare indication [ 30 , 31 ]. Thus, doxorubicin remains an established primary systemic treatment in a palliative context, yielding response rates that span from 16% to 27% along with a median survival of around 18 months from the commencement of first-line systemic therapy [ 2 ].…”

PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas

“…However, SS18::SSX has been so far very difficult to target for therapeutic intervention [75]. Thus, other targeted therapy-based approaches acting at epigenetic levels have been tested in preclinical and clinical settings, including enhancer of zeste homolog 2 (EZH2) and histone deacetylase (HDAC) inhibitors [141]. However, despite promising preclinical results, phase II clinical trials reported no objective response after treatment with vorinostat, panobinostat (two HDAC inhibitors; NCT00918489, NCT01136499), or tazemetostat (EZH2 inhibitor; NCT02601950).…”