• Eddy Pasquier, Nicolas André, Janine Street, Anuradha Chougule, Bharat Rekhi, Jaya Ghosh, Deepa S J Philip, Marie Meurer, Karen L MacKenzie, Maria Kavallaris, and Shripad D Banavali.
• INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille, France; Metronomics Global Health Initiative, Marseille, France; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia. Electronic address: epasquier@ccia.unsw.edu.au.
• EBioMedicine. 2016 Apr 1; 6: 87-95.

BackgroundAngiosarcomas are rare malignant tumors of vascular origin that represent a genuine therapeutic challenge. Recently, the combination of metronomic chemotherapy and drug repositioning has been proposed as an attractive alternative for cancer patients living in developing countries.MethodsIn vitro experiments with transformed endothelial cells were used to identify synergistic interactions between anti-hypertensive drug propranolol and chemotherapeutics. This led to the design of a pilot treatment protocol combining oral propranolol and metronomic chemotherapy. Seven consecutive patients with advanced/metastatic/recurrent angiosarcoma were treated with this combination for up to 12months, followed by propranolol-containing maintenance therapy.FindingsGene expression analysis showed expression of ADRB1 and ADRB2 adrenergic receptor genes in transformed endothelial cells and in angiosarcoma tumors. Propranolol strongly synergized with the microtubule-targeting agent vinblastine in vitro, but only displayed additivity or slight antagonism with paclitaxel and doxorubicin. A combination treatment using bi-daily propranolol (40mg) and weekly metronomic vinblastine (6mg/m(2)) and methotrexate (35mg/m(2)) was designed and used in 7 patients with advanced angiosarcoma. Treatment was well tolerated and resulted in 100% response rate, including 1 complete response and 3 very good partial responses, based on RECIST criteria. Median progression-free and overall survival was 11months (range 5-24) and 16months (range 10-30), respectively.InterpretationOur results provide a strong rationale for the combination of β-blockers and vinblastine-based metronomic chemotherapy for the treatment of advanced angiosarcoma. Furthermore, our study highlights the potential of drug repositioning in combination with metronomic chemotherapy in low- and middle-income country setting.FundingThis study was funded by institutional and philanthropic grants.Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

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