Targeting the Epigenetic Engine of Synovial Sarcoma: Advancing Therapeutic Innovation With AACR Donor Support

Synovial sarcoma (SS) is a rare but aggressive subtype of soft tissue sarcoma, accounting for approximately 10% of cases. It is uniquely identified by the SS18::SSX fusion oncoprotein, which results from a chromosomal translocation. This fusion protein integrates into SWI/SNF chromatin remodeling complexes, displacing native subunits and redirecting the complex to developmental genes that are typically repressed by Polycomb group proteins. This misdirection leads to widespread transcriptional dysregulation and oncogenic activation (1).

SS typically occurs in the lower extremities and is prone to infiltration of nearby tissues. Standard care includes surgery, chemotherapy, and radiotherapy, which can be promising for localized disease; however, due to lack of effective targeted therapies, high rates of recurrence, and metastasis, SS remains difficult to treat, offering limited long-term benefits with a 5-year survival rate of only 40-50% (2). Given the universal presence of SS18::SSX in SS and its absence in other cancers, targeting the epigenetic machinery associated with this fusion protein presents a highly selective and promising therapeutic strategy.

Yao Yu, PhD, a postdoctoral associate at Duke University, is leading efforts to uncover such vulnerabilities. Her research is supported by the 2024 AACR Sarcoma Research Fellowship, which was made possible through end-of-year contributions from individual donors to the AACR. This fellowship has been instrumental in advancing her work to identify and validate novel epigenetic targets in SS using CRISPR-Cas9 screening, genomic profiling, multi-omics approaches, and proteolysis targeting chimera (PROTAC) technology. 

In a recent Science Advances publication, Dr. Yu and colleagues identified WDR5 as a critical vulnerability in SS and demonstrated its potential as a novel therapeutic target for this aggressive soft tissue sarcoma (2). WDR5 is a highly conserved chromatin regulator and core component of the KMT2/MLL family of histone methyltransferases, which catalyze histone H3K4 methylation, a key epigenetic marker of active gene transcription. WDR5 sustains oncogenic expression, cancer stem cell maintenance, and promotes cell cycle progression and proliferation (3).

Dr. Yu found that WDR5 knockdown significantly impaired SS cell proliferation and colony formation, with minimal effects on non-SS cells. Further, co-immunoprecipitation and immunofluorescence studies revealed that WDR5 physically interacts with SS18::SSX fusion protein and SWI/SNF chromatin remodeling components, an interaction specific to SS cells (2).

After validating WDR5 as an essential dependency and vulnerable target in SS, Dr. Yu demonstrated that pharmacological degradation of WDR5 using a novel PROTAC, MS67, reduced chromatin occupancy of SS18::SSX and associated SWI/SNF subunits (e.g., BAF155) without altering their protein levels. Conversely, SS18::SSX knockdown diminished WDR5 chromatin binding, indicating a mutual dependency. Treatment with MS67 also led to global reduction of H3K4me2/3 at WDR5-bound loci, particularly at developmental and ribosomal protein genes, many of which are co-occupied by SS18::SSX and BAF155.

Transcriptomic analysis revealed that WDR5 degradation downregulated SS18::SSX target genes and activated p53 signaling. MS67 treatment also induced apoptosis and senescence via p53 and p21 activation, effects that were partially rescued by p53 knockdown. In SS xenograft models, MS67 significantly suppressed tumor growth and extended survival without observable toxicity. Tumors from mice treated with MS67 showed a reduced expression of WDR5 targets and increased markers of apoptosis and p53 activation.

This study identified WDR5 as a functional partner of SS18::SSX, essential for maintaining oncogenic transcriptional programs in SS. By leveraging PROTAC technology, Dr. Yu demonstrated that selective degradation of WDR5 disrupts this epigenetic axis and impairs tumor growth both in vitro and in vivo. The 2024 AACR Sarcoma Research Fellowship, made possible through donor generosity, has been pivotal in enabling this research. It exemplifies how philanthropic support can accelerate discoveries that may transform cancer treatment.

Reflecting on the impact of the fellowship, Dr. Yu shared, “It significantly advanced my research and career. The support enabled us to explore epigenetic vulnerabilities in SS, identify novel therapeutic targets, and validate them using genomic profiling and mouse models. Our goal is to improve diagnosis and develop targeted therapies that enhance patient care. This grant not only empowers our team but also brings us closer to making a meaningful impact on the lives of those affected by this challenging condition.”

Looking ahead, Dr. Yu plans to explore combination therapies involving WDR5 degraders with p53 activators and chromatin remodeling inhibitors. While her current focus is SS, the broader implications extend to other fusion-driven and chromatin-dysregulated cancers. The discovery that WDR5 degradation induces ribosomal stress and p53 activation suggests a conserved vulnerability that could inform future precision oncology strategies across tumor types. This work not only uncovers a novel, druggable epigenetic vulnerability in SS but also exemplifies how precision degradation of chromatin regulators can rewire oncogenic programs, offering a transformative strategy for targeting fusion-driven cancers.

References:

1. Nielsen TO, Poulin NM, Ladanyi M. Synovial sarcoma: recent discoveries as a roadmap to new avenues for therapy. Cancer Discov. 2015 Feb;5(2):124-34. doi: 10.1158/2159-8290.CD-14-1246.
2. Yu Y, Yu X, Pan B, Chan HM, Kaniskan HÜ, Jin J, et al. Pharmacologic degradation of WDR5 suppresses oncogenic activities of SS18::SSX and provides a therapeutic of synovial sarcoma. Sci Adv. 2025 Apr 25;11(17):eads7876. doi: 10.1126/sciadv.ads7876.
3. Rao RC, Dou Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat Rev Cancer. 2015 Jun;15(6):334-46. doi: 10.1038/nrc3929