Combined treatment using repurposed synthetic peptide desmopressin and bevacizumab as a potential antiangiogenic strategy in osteosarcoma.

Background: Osteosarcoma (OSA) is the most common primary malignant bone tumor and is characterized by high mortality, early metastatic dissemination, and extensive vascularization. Although overexpression of Vascular Endothelial Growth Factor A (VEGF-A) is associated with poor prognosis, clinical responses to the anti-VEGF-A monoclonal antibody Bevacizumab (BEVA) have been limited. Desmopressin (dDAVP), a hemostatic agent that acts as a selective arginine vasopressin receptor 2 (AVPR2) agonist, has demonstrated antitumor and angiostatic properties in other malignancies, however, its role in OSA remains incompletely characterized. This study evaluated the therapeutic potential of dDAVP as a coadjuvant strategy to enhance BEVA efficacy in OSA. Methods: Bioinformatic analyses of AVPR2 expression and its associations with tumor aggressiveness, immune and stromal infiltration markers, and clinical outcomes were performed using TCGA-SARC and TARGET-OS datasets. Endothelial proliferation, migration, and morphogenesis were assessed in HmVEC-L and HMEC-1 microvascular cells. Antitumor activity was evaluated in human (MG-63) and murine (K7M3) OSA models. Results: Exploratory transcriptomic analyses revealed that AVPR2 expression was inversely associated with proangiogenic, prosurvival, and prometastatic gene signatures, while positively correlating with immune and stromal infiltration markers. Elevated AVPR2 expression was also associated with improved survival in both the pan-sarcoma cohort and a pediatric OSA subset. dDAVP significantly reduced pulmonary metastasis and OSA-driven vascularization Conclusion: These findings support further translational evaluation of dDAVP as a potential adjuvant therapy in OSA, particularly in combination with BEVA. By targeting complementary angiogenesis-related mechanisms, this dual antiangiogenic strategy may improve therapeutic efficacy in OSA.