Abstract 3062: Drug repurposing of β-blocker propranolol and hemostatic compound desmopressin in osteosarcoma: Preclinical antitumor activity on 2D and 3D cell growth, chemotaxis and xenograft progression

Abstract

Abstract Introduction. Osteosarcoma (OS) is the most common malignant primary bone tumor in children and young adults, with alarmingly elevated mortality rates, especially in developing countries. OS patients bear highly invasive and vascularized tumors, with limited response to standard of care (SoC) therapies, and are in urgent need of novel therapeutic strategies. Propranolol (PPN) is a non-selective β-adrenergic receptor (β-AR) antagonist originally used in the treatment of diverse heart diseases. On the other hand, desmopressin (dDAVP) is a hemostatic drug that acts as a selective agonist for the vasopressin type-2 receptor (AVPR2) present in blood microvessels and several tumor types. Given that β-ARs and AVPR2 signalling regulates many cellular processes involved in the initiation and progression of cancer, multiple efforts have been made to repurpose PPN and dDAVP in indications such as breast and colorectal cancer, melanoma and angiosarcoma, among others. Considering the unsatisfied clinical needs of OS, the objective of this work was to evaluate the in vitro/in vivo antitumoral activity of PPN and dDAVP on highly aggressive preclinical models of OS. Materials and methods. The human OS cell lines MG-63 and U2-OS were used for in vitro or in vivo experiments. Target expression was assessed by qPCR and immunohistochemistry. Sensitivity to PPN or dDAVP was evaluated by in vitro 72 h proliferation, 7 d clonogenic growth, 3D spheroid formation, transwell chemotaxis assays and MG-63 xenograft progression in nude mice. In addition, PPN was evaluated as monotherapy or in combination with SoC chemotherapy. Results. PPN (10-100 µM) and dDAVP (0.1-10 µM) drastically reduced clonogenic and 3D growth, migration, mitotic index and proliferation of β-AR and AVPR2-expressing OS cells (p<0.05). Synergistic antitumoral effects were observed after combining PPN with cisplatin or methotrexate, in vitro and in vivo (CI<1). In animals bearing growing OS s.c. xenografts sustained treatment during 4 weeks with PPN (10 mg/kg i.p. daily) or dDAVP (12 µg/kg i.v. three times a week) markedly abrogated tumor progression, exhibiting modulation of local tumor aggressiveness and reducing final tumor burden by 25 or 45%, respectively (p<0.01). Conclusions. Taking into account PPN and dDAVP robust antitumoral effects, β-ARs antagonization or agonist activation of AVPR2 are achievable and interesting therapeutic approaches to modulate OS tumor aggressiveness. Both agents could be proposed as coadyuvant agents for treating OS, not only in combination with chemotherapy but also administered during the perioperative setting. Citation Format: Luisina Solerno, Natasha Sobol, Rocío Rodriguez, Marina Pifano, Giselle Ripoll, Hernan Farina, Liliana Vasquez, Daniel F. Alonso, Juan Garona. Drug repurposing of β-blocker propranolol and hemostatic compound desmopressin in osteosarcoma: Preclinical antitumor activity on 2D and 3D cell growth, chemotaxis and xenograft progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3062.