Eddy Pasquier a , b , c , * , Nicolas André a , b , d , Janine Street c , Anuradha Chougule e , Bharat Rekhi f , Jaya Ghosh e , Deepa S.J. Philip e , Marie Meurer a , g , Karen L. MacKenzie c , Maria Kavallaris c , h , Shripad D. Banavali b , e , **
17 February 2016
Angiosarcomas 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.
In 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 12 months, followed by propranolol-containing maintenance therapy.
Gene 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 (40 mg) and weekly metronomic vinblastine (6 mg/m 2) and methotrexate (35 mg/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 11 months (range 5–24) and 16 months (range 10–30), respectively.
Our 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.
A strong synergism was identified between propranolol and vinblastine in an in vitro model of angiosarcoma.
Adrenergic receptor expression was detected in angiosarcoma tumors providing a molecular target for propranolol.
Propranolol and vinblastine-based metronomic chemotherapy led to 100% response in 7 patients with inoperable angiosarcoma.
This treatment resulted in prolonged survival of angiosarcoma patients and warrants further investigation in larger trials.