Osteosarcoma: prognosis plateau warrants retinoblastoma pathway targeted therapy

Abstract

Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents, affecting ~560 young patients in the United States annually. The term OS describes a diverse array of subtypes with varying prognoses, but the majority of tumors are high grade and aggressive. Perhaps because the true etiology of these aggressive tumors remains unknown, advances in OS treatment have reached a discouraging plateau, with only incremental improvements over the past 40 years. Thus, research surrounding the pathogenesis of OS is essential, as it promises to unveil novel therapeutic targets that can attack tumor cells with greater specificity and lower toxicity. Among the candidate molecular targets in OS, the retinoblastoma (RB) pathway demonstrates the highest frequency of inactivation and thus represents a particularly promising avenue for molecular targeted therapy. This review examines the present thinking and practices in OS treatment and specifically highlights the relevance of the RB pathway in osteosarcomagenesis. Through further investigation into RB pathway-related novel therapeutic targets, we believe that a near-term breakthrough in improved OS prognosis is possible.

KDM5 demethylases and their role in cancer cell chemoresistance

“…KDM5A acts also as a repressor of metabolic regulatory genes, its ablation restores differentiation in pRB−/− cells via increasing mitochondrial respiration. KDM5A inhibition is therefore a potential therapeutic approach for pRB−/− cells, such a osteosarcoma, which would restore mitochondrial function and differentiation . Subsequently, there were found other interactions, with the Polycomb complex, which play important role in maintaining gene silencing during development and tissue homeostasis and with the Sin3 corepressor complex .…”

“…KDM5A inhibition is therefore a potential therapeutic approach for pRB−/− cells, such a osteosarcoma, which would restore mitochondrial function and differentiation. 14,15 Subsequently, there were found other interactions, with the Polycomb complex, which play important role in maintaining gene silencing during development and tissue homeostasis and with the Sin3 corepressor complex. 10,16 Moreover KDM5A is an integral, conserved component of the Notch/RBP-J repressor complex, 17 and it is a fundamental element in the switch-off process of the Notch target genes.…”

SUMO‑specific protease 2 (SENP2) functions as a tumor suppressor in osteosarcoma via SOX9 degradation

“…Osteosarcoma (OS) and the Ewing sarcoma family of tumors (ESFT) are the most common primary bone malignancies observed in children and adolescents worldwide (1). OS is an osteoid-producing malignancy of mesenchymal origin that accounts for <0.2% of all cancers (2). However, the frequency of OS has been increasing by 0.3% per year over the last 10 years (2).…”

“…OS is an osteoid-producing malignancy of mesenchymal origin that accounts for <0.2% of all cancers (2). However, the frequency of OS has been increasing by 0.3% per year over the last 10 years (2). OS occurs most frequently in patients between 5 years of age and early adulthood (2).…”

“…However, the frequency of OS has been increasing by 0.3% per year over the last 10 years (2). OS occurs most frequently in patients between 5 years of age and early adulthood (2). Unfortunately, few improvements have been made in prognostic and therapeutic methods (3,4).…”