Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma

SIMPLE SUMMARY: The efficacy of current osteosarcoma therapy is diminished by two adverse events, namely resistance to chemotherapy and metastatic dissemination. In recent decades, research has been devoted to reducing these adverse events. Inhibiting bone resorption has shown promising effects on metastatic dissemination and tumor growth, with, however, the formation of significant tumoral mineralized tissue. Endothelin signaling is implicated in activating the cell that forms the mineralized tissues, consequently the impact of inhibiting it alone and in combination with the inhibition of bone resorption was evaluated using osteosarcoma models. The results obtained showed that inhibiting endothelin signaling significantly reduced the formation of mineralized tumor tissue concomitantly to metastatic dissemination without affecting sensitivity to chemotherapy. This inhibition appears to be a promising new therapeutic tool in the fight against osteosarcoma. ABSTRACT: Current treatments for osteosarcoma, combining conventional polychemotherapy and surgery, make it possible to attain a five-year survival rate of 70% in affected individuals. The presence of chemoresistance and metastases significantly shorten the patient’s lifespan, making identification of new therapeutic tools essential. Inhibiting bone resorption has been shown to be an efficient adjuvant strategy impacting the metastatic dissemination of osteosarcoma, tumor growth, and associated bone destruction. Unfortunately, over-apposition of mineralized matrix by normal and tumoral osteoblasts was associated with this inhibition. Endothelin signaling is implicated in the functional differentiation of osteoblasts, raising the question of the potential value of inhibiting it alone, or in combination with bone resorption repression. Using mouse models of osteosarcoma, the impact of macitentan, an endothelin receptor inhibitor, was evaluated regarding tumor growth, metastatic dissemination, matrix over-apposition secondary to RANKL blockade, and safety when combined with chemotherapy. The results showed that macitentan has no impact on tumor growth or sensitivity to ifosfamide, but significantly reduces tumoral osteoid tissue formation and the metastatic capacity of the osteosarcoma. To conclude, macitentan appears to be a promising therapeutic adjuvant for osteosarcoma alone or associated with bone resorption inhibitors.