Advancements in Osteosarcoma Therapy: Overcoming Chemotherapy Resistance and Exploring Novel Pharmacological Strategies

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(4), P. 520 - 520

Published: April 3, 2025

Osteosarcoma is recognized as the most prevalent primary bone malignancy, primarily affecting children and adolescents. It characterized by its aggressive behavior high metastatic potential, which often leads to poor patient outcomes. Despite advancements in surgical techniques chemotherapy regimens, prognosis for patients with osteosarcoma remains unsatisfactory, survival rates plateauing over past few decades. A significant barrier effective treatment development of resistance, complicates management disease contributes recurrence. This review article aims provide a comprehensive overview recent therapy, particularly overcoming resistance. We begin discussing current standard modalities, including resection conventional agents such methotrexate, doxorubicin, cisplatin. While these approaches have been foundational managing osteosarcoma, they are limited adverse effects variability efficacy among patients. To address challenges, we explore novel pharmacological strategies that aim enhance includes targeted therapies focusing on specific molecular alterations cells immunotherapeutic designed harness body’s immune system against tumors. Additionally, innovative drug delivery systems improve bioavailability existing treatments while minimizing toxicity. The also assesses mechanisms underlying efflux mechanisms, altered metabolism, enhanced DNA repair pathways. By synthesizing research findings, highlight potential new therapeutic resistance mechanisms. Ultimately, this seeks inform future directions clinical practices, underscoring need continued innovation treating outcomes rates.

Language: Английский

Development and optimization of Eva1 (MPZL2) targeting chimeric antigen receptor T cells

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(5), P. e009825 - e009825

Published: May 1, 2025

Background Whereas chimeric antigen receptor gene modified T (CAR-T) cell therapy has been clinically applied to malignant lymphomas and multiple myeloma, CAR-T for solid tumors so far not reached clinical application. Epithelial V-like 1 (Eva1), transcribed from myelin protein zero-like 2 (MPZL2), is a small surface highly expressed on various tumor cells. We selected Eva1 as novel tumor-target because of its broad expression across types. The purpose the present study develop optimize cells targeting Eva1. Method prepared humanized single chain variable fragment sequences based mouse anti-human monoclonal antibody. constructed six Eva1CAR-Ts one that maintained specificity good cellular proliferation after stimulation. further optimized length extracellular spacer domain choice intracellular in vitro two different xenograft models. Results confirmed lines by flow cytometry analysis public database, but we also observed normal monocytes weakly A combination short 4-1BB or CD79A/CD40 provided higher treatment efficacy both vivo. cytokine release autologous monocyte stimulation Eva1CAR-T was comparable B CD19CAR-T Humanized demonstrated excellent therapeutic infusing dose (1×10 6 ) NCI-H1975 lung cancer CFPAC-1 pancreatic line grafted model. Conclusions In summary, these data suggest promising potential Eva1-positive tumors. Regarding on-target/off-tumor recognition, detailed analyses responses tissues are needed.

Language: Английский

CD49d promotes T‐cell senescence in chronic lymphocytic leukaemia

British Journal of Haematology, Journal Year: 2025, Volume and Issue: unknown

Published: May 15, 2025

Summary While CD49d (α4 integrin) is an established prognostic marker in chronic lymphocytic leukaemia (CLL) and associated with aggressive disease, its impact on T‐cell biology remains poorly understood. Compared to healthy donors, CLL patients exhibited significantly elevated expression both CD4+ CD8+ T cells ( p < 0.001) as detected by flow cytometry, which was also confirmed the single‐cell RNA sequencing (scRNA‐seq) 0.001). Differentially expressed genes CD49d+ (both cells) versus CD49d− identified were enriched cellular senescence pathways, while this phenomenon absent individuals. Functional validation demonstrated that displayed senescence‐associated markers (e.g. interferon‐gamma, granzyme B) a shift towards memory phenotypes, correlating immunosuppressive signatures. This discovery suggests targeting CD49d‐dependent pathways may reverse dysfunction immunotherapy.

Language: Английский