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

Abstract

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. In vivo activity was assessed using xenogeneic and syngeneic models of tumor growth, metastasis, and tumor-associated angiogenesis. Combined dDAVP + BEVA therapy was evaluated in vitro and in vivo. Histopathological endpoints included mitotic index, desmoplasia, vimentin expression, and tumor necrosis.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 in vivo and inhibited endothelial proliferation, migration, and morphogenesis in vitro. Under tumor-conditioned conditions, dDAVP enhanced the antivascular activity of BEVA. Combined treatment with clinically relevant doses of dDAVP and BEVA significantly inhibited OSA xenograft progression without overt toxicity and favorably modulated histopathological markers of tumor aggressiveness.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.