(P 332) ENHANCING THERAPEUTIC EFFICACY IN SYNOVIAL SARCOMA BY TARGETING P53-MDM2 AXIS AND HDAC PATHWAYS

Objective: Synovial sarcoma (SS) is a rare malignancy, accounting for about 8-10% soft tissue sarcomas (STS). It involves a t(X;18) chromosomal translocation that creates a fusion gene SS18-SSX. Synovial sarcoma exhibits a tendency to progress slowly, often accompanied by a notable incidence of late-stage metastasis, occurring in approximately 50% of all cases and resistance to conventional therapies. MDM2 is a negative regulator of p53. The inhibition of the p53-MDM2 interaction is a promising strategy to trigger p53-mediated apoptosis in tumor. Besides that, Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. The objective of this study is to investigate the treatment of HDM201 which is a selective inhibitor for p53-MDM2 interaction and Panobinostat, a histone deacetylase (HDAC) inhibitor. Furthermore, the efficacy of combining HDM201 and Panobinostat in treating synovial sarcoma will be evaluated to determine if targeting the p53-MDM2 interaction and histone deacetylase pathways simultaneously enhances tumor cell apoptosis and inhibits growth more effectively than either treatment alone. This approach has the potential to overcome resistance mechanisms and improve patient outcomes.

Methods: To investigate the effects of HDM201 and Panobinostat in synovial sarcoma, we conducted proliferation assays to determine the IC50 values for SS cell lines and assessed the synergistic effects of combination treatment. We measured the growth curves of synovial sarcoma mouse tumors treated with either HDM201, Panobinostat alone, or their combination. Tumor samples from treated and vehicle groups were collected and subjected to RNA-seq analysis to examine the molecular impacts of the treatments. We also involved genetic disruptions of Trp53 to investigate its role in SS tumorigenesis. Histological morphologies of tumors were scored and RNA-seq analysis was performed to examine how Trp53 mutations might influence the transcriptional signature of synovial sarcoma.

Results: Our results showed that MDM2, MDM4 amplification and Trp53 mutation are mutually exclusive in synovial sarcoma. However, the DepMap study highlights the crucial dependency of MDM2 and MDM4 for SS cells growth. Genetic mutation of Trp53 accelerate the tumor growth, but did not change the synovial sarcoma transcriptional signature. Besides that, SS tumor with Trp53 mutation intend to have more biphasic morphology compare with tumor only express SS18:SSX. Tumors received either HDM201, Panobinostat alone showed slower tumor growth compared with vehicle controls but the differences were not statistically significant. However, the combination treatment significantly suppressed tumor growth. RNA-seq analysis indicates that the combination treatment has a synergistic effect on inducing cell cycle arrest.

Conclusion: HDM201 and Panobinostat alone demonstrated modest effects on tumor growth, their combination significantly suppressed tumor progression, indicating a synergistic effect in inducing cell cycle arrest as observed through RNA-seq analysis. This study underscores the potential of targeting the p53-MDM2 interaction and HDAC pathways simultaneously to enhance apoptosis and inhibit growth in synovial sarcoma, offering promising avenues for overcoming resistance mechanisms and improving patient outcomes.