Targeting aggressive osteosarcoma with a peptidase-enhanced cytotoxic melphalan flufenamide

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Metastatic high-grade osteosarcoma (HGOS) has dismal survival rates, with limited progress over 30 years.
• Aminopeptidase N (ANPEP) is implicated in HGOS progression.
• Melphalan flufenamide (melflufen) is a novel lipophilic peptidase-enhanced cytotoxic agent.

Purpose of the Study:

• To investigate the role of ANPEP in HGOS.
• To evaluate melflufen's efficacy in targeting HGOS, particularly in metastatic settings.

Main Methods:

• Meta-analysis of gene expression data to correlate ANPEP levels with metastasis-free survival in HGOS.
• Ex vivo and in vitro testing of melflufen and standard chemotherapeutics in HGOS models.
• In vivo studies to assess melflufen's anti-tumor and anti-metastatic effects.

Main Results:

• Elevated ANPEP expression significantly correlates with reduced metastasis-free survival in HGOS patients.
• Melflufen demonstrated anti-proliferative activity in HGOS cell lines and patient-derived models, including drug-resistant ones.
• Melflufen rapidly induced apoptosis in HGOS cells, with sensitivity linked to high ANPEP expression.
• Melflufen showed synergy with doxorubicin and exhibited anti-tumor and anti-metastatic effects in vivo.

Conclusions:

• Melflufen exhibits significant anti-cancer activity in HGOS models.
• Melflufen's efficacy is associated with ANPEP expression.
• Melflufen holds promise as an adjuvant therapy, potentially combined with doxorubicin, to enhance treatment outcomes for metastatic HGOS.