Dr Randall on the Role of EZH2 in Doxorubicin Resistance in Soft Tissue Sarcoma

R. Lor Randall, MD, FACS, David Linn Endowed Chair for Orthopedic Surgery, chair, Department of Orthopedic Surgery, professor, University of California (UC) Davis Comprehensive Cancer Center, discusses the role of EZH2 in doxorubicin resistance in soft tissue sarcoma.

An investigation conducted in the lab of Janai R. Carr-Ascher, MD PhD, of UC Davis Comprehensive Cancer Center examined the correlation between the abundance of soft tissue sarcoma cancer stem cells and resistance to doxorubicin, Randall explains. The study used patient-derived stem cell samples from the 5 soft tissue sarcoma subtypes.

Randall notes that a key finding was the identification of EZH2, a member of the polycomb repressive complex 2 (PRC2) responsible for H3K27 methylation, which plays a crucial role in the epigenetic regulation of gene expression in cancer stem cells. EZH2 activity was observed across all 5 soft tissue sarcoma subtypes, suggesting its involvement in the mechanisms underlying doxorubicin resistance, Randall says.

Given these findings, EZH2 has emerged as a potential therapeutic target for overcoming doxorubicin resistance in patients with soft tissue sarcoma. Randall notes that tazemetostat (Tazverik), an EZH2 inhibitor, could represent a potential therapeutic option for patients with soft tissue sarcoma that is resistant to doxorubicin. In January 2020, the FDA approved tazemetostat for the treatment of patients 16 years of age and older with metastatic or locally advanced epithelioid sarcoma who are not eligible for complete resection.

Randall emphasizes the importance of further research to explore the efficacy of targeting EZH2 in this context, with the goal of developing new therapeutic strategies that could be tested in clinical trials. Further research and potentially a clinical trial will examine the use of tazemetostat in patients with doxorubicin-resistant soft tissue sarcoma, he concludes.