Targeting USP7 in sarcomas: opportunities and challenges

Sarcomas are a heterogeneous group of aggressive mesenchymal tumors with limited therapeutic options in the advanced setting. Novel actionable targets and biology-driven therapies are needed to improve patients' outcome. The identification of common pathways engaged by different disease drivers may suggest new therapeutic strategies exploitable across sarcomas. Deregulation of the ubiquitin-proteasome system (UPS) has provided attractive targets for therapeutic intervention also in these malignancies. As sarcoma cells hijack UPS to stabilize aberrant oncogenic signaling and/or inactivate tumor suppressors, the identification of additional components contributing to the UPS deregulation may suggest novel avenues to switch off undruggable drivers and non-oncogene dependencies. In this view, ubiquitin specific proteases (USPs), the largest subfamily of deubiquitinases, are emerging as vulnerabilities in several sarcoma subtypes. This review focuses on USP7 a key deubiquitinase in cancer and one of the most investigated. Current knowledge regarding USP7 expression/function, known and putative substrates crucially implicated in the growth and progression of selected sarcomas (e.g., osteosarcoma, synovial, Ewing's and Kaposi's sarcoma) is illustrated. Preclinical findings addressing the pathobiological role of USP7 and highlighting its potential as therapeutic target are summarized. Given the participation of USP7 in tumor immune evasion, the opportunity to exploit the expanding armamentarium of USP7 inhibitors to reactivate antitumor immunity in "immunological cold" sarcomas, is argued. Some aspects worthy of in-depth investigation to fully harness the multitargeting potential of anti-USP7 agents, bypass possible limitations, overcome resistance mechanism and design rationale combination are commented.