Telomere as a Therapeutic Target in Dedifferentiated Liposarcoma

SIMPLE SUMMARY: DDLPS is a non-lipogenic tumor with aggressive clinical behavior. DDLPS patients have limited therapeutic options, especially those with retroperitoneal tumors, and their outcome remains largely unsatisfactory, highlighting the need for novel treatment strategies. Gene expression analysis carried out in clinical samples from primary retroperitoneal DDLPS indicated that these tumors highly express genes involved in telomere maintenance, the cellular process that guarantees immortality to tumor cells. In this study, we evaluated the effect of RHPS4, a molecule able to alter telomere by binding to telomeric structures called G-quadruplexes, in patient-derived DDLPS cell lines. Exposure to RHPS4 induced DNA damage and decreased cell proliferation and migration, thus suggesting telomere as a novel target and G-quadruplex binders as innovative therapeutic agents in DDLPS. ABSTRACT: Background: Well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS) accounts for ~60% of retroperitoneal sarcomas. WDLPS and DDLPS divergently evolve from a common precursor and are both marked by the amplification of the 12q13–q15 region, leading to the abnormal expression of MDM2, CDK4, and HMGA2 genes. DDLPS is a non-lipogenic disease associated with aggressive clinical behavior. Patients have limited therapeutic options, especially for advanced disease, and their outcome remains largely unsatisfactory. This evidence underlines the need for identifying and validating DDLPS-specific actionable targets to design novel biology-driven therapies. Methods: Following gene expression profiling of DDLPS clinical specimens, we observed the up-regulation of “telomere maintenance” (TMM) pathways in paired DD and WD components of DDLPS. Considering the relevance of TMM for LPS onset and progression, the activity of a telomeric G-quadruplex binder (RHPS4) was assessed in DDLPS patient-derived cell lines. Results: Equitoxic concentrations of RHPS4 in DDLPS cells altered telomeric c-circle levels, induced DNA damage, and resulted in the accumulation of γ-H2AX-stained micronuclei. This evidence was paralleled by an RHPS4-mediated reduction of in vitro cell migration and induction of apoptosis/autophagy. Conclusions: Our findings support telomere as an intriguing therapeutic target in DDLPS and suggest G-quadruplex binders as innovative therapeutic agents.