Telomere as a Therapeutic Target in Dedifferentiated Liposarcoma

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.

Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma

“…Novel drugs designed to simultaneously inhibit both MDM2 and MDMX represent an area of active research. In addition, alternative targets amplified on the 12q arm, including CDK4 , HMGA2 , and YEATS4 , are also being investigated for combination therapies ( 223 , 224 ). Advancements in peptide synthesis and cell-free DNA represent promising future directions in the targeted treatment and surveillance of these tumors.…”

Telomeres and Telomerase as Promising Targets for Malaria Therapy: A Comprehensive Review

“…However, the efforts have not been enough to protect cellular senescence and death in malaria. The mechanisms governing telomere length maintenance are currently under active area of research, as aberrations in these mechanisms have been associated with variety of human ailment, including cancer [132,133], cardiovascular and nervous disorders [125], and malaria [72,73,89]. Notably, the Plasmodium parasite employs telomerase to maintain the length of its telomeres during replication [13,37].…”

Telomere-related DNA damage response pathways in cancer therapy: prospective targets

“…G4 ligands inhibit telomerase binding to telomeric DNA, eventually inhibiting telomerase activity ( Tiek et al, 2022 ). G4-stabilizing ligands include telomeric repressors, TMPyP4, RHPS4, pyridostatin and telomestatin ( Teng et al, 2021 ; Alessandrini et al, 2022 ; Liu LY. et al, 2022 ; Iida et al, 2022 ).…”