OS Therapies to Present at BioFuture 2025 and Discuss OST-HER2 Clinical Development

Key Unmet Needs and Target Populations for Osteosarcoma

Major Unmet Clinical Needs

Metastatic osteosarcoma remains a significant challenge with survival rates remaining low despite surgery and chemotherapy, indicating a need for new therapeutic approaches. Patients with metastatic and recurrent osteosarcoma have particularly poor prognosis, highlighting an urgent need to develop innovative approaches to address the complex challenges of this disease.

Chemoresistance is a major treatment challenge, with research exploring underlying molecular mechanisms such as the novel fusion gene RPS27-RPS24 that enhances glutaminase-mediated glutamine metabolism. The development of drug resistance continues to limit treatment efficacy, as evidenced by unclear mechanisms associated with regorafenib resistance.

Despite persistent research endeavors, there has been limited amelioration in the five-year survival rate for osteosarcoma, indicating current therapeutic strategies are inadequate in addressing clinical necessities.

Target Populations and Emerging Approaches

Patients not achieving favorable necrosis (≥90%) following neoadjuvant chemotherapy demonstrate inferior event-free survival and overall survival, representing a critical target population. Research indicates that patients with smaller tumors (≤10 cm), lower serum alkaline phosphatase (≤450 IU/L), and who had earlier surgery (<115 days) are more likely to achieve favorable necrosis.

Refractory bone and soft tissue sarcoma patients, including those with osteosarcoma, are being targeted for treatment with novel agents such as anlotinib, which has shown encouraging efficacy and favorable tolerability.

Emerging Research Directions

Epigenetic changes, particularly histone H3 methylation, are being investigated, with the histone lysine demethylase inhibitor IOX-1 showing promise by dose-dependently increasing histone H3 methylation and inhibiting cellular migratory and invasive capabilities.

Metabolic reprogramming in osteosarcoma represents a potential therapeutic target, while maintenance therapy, particularly antiangiogenic approaches such as metronomic chemotherapy, is under investigation.

Self-assembled supramolecular drugs based on small-molecule anion transporters are being developed, showing excellent targeted anticancer therapy against subcutaneous xenograft tumor and lung metastasis models.

Research Gaps

The underlying mechanisms of osteosarcoma are mainly unknown, requiring further investigation. Molecular signals related to carcinogenesis and tumor progression, such as Enhancer of zeste homologue 2 (EZH2) and NOTCH pathway, are not fully understood.

Challenges such as tumor heterogeneity, immune evasion, and the immunosuppressive tumor microenvironment (TME) persist in osteosarcoma treatment, with novel approaches being explored including dual-targeting, armored CAR-T cells, and combination therapies with immune checkpoint inhibitors and ferroptosis inducers.

Critical challenges in maintenance therapy include optimizing drug selection, treatment duration, and patient stratification to maximize benefits for osteosarcoma patients.