Abstract
Patients with metastatic angiosarcoma undergoing chemotherapy, radiation, and/or surgery experience a median progression free survival of less than 6 months and a median overall survival of less than 12 months. Given the aggressive nature of this cancer, angiosarcoma clinical responses to chemotherapy or targeted therapeutics are generally very poor. Inhibition of beta adrenergic receptor (β-AR) signaling has recently been shown to decrease angiosarcoma tumor cell viability, abrogate tumor growth in mouse models, and decrease proliferation rates in preclinical and clinical settings. In the current study we used cell and animal tumor models to show that β-AR antagonism abrogates mitogenic signaling and reduces angiosarcoma tumor cell viability, and these molecular alterations translated into patient tumors. We demonstrated that non-selective β-AR antagonists are superior to selective β-AR antagonists at inhibiting angiosarcoma cell viability. A prospective analysis of non- selective β-AR antagonists in a single arm clinical study of metastatic angiosarcoma patients revealed that incorporation of either propranolol or carvedilol into patients' treatment regimens leads to a median progression free and overall survival of 9 and 36 months, respectively. These data suggest that incorporation of non-selective β-AR antagonists into existing therapies against metastatic angiosarcoma can enhance clinical outcomes.
Highlights
Angiosarcomas are rare vascular tumors of aberrant endothelial histology that exhibit an aggressive and often highly lethal natural course
To determine if a similar outcome could be observed in angiosarcoma models, we evaluated the viability of two angiosarcoma cell lines following treatment with propranolol, β1-AR selective antagonists, or β2-AR selective antagonists. β3-AR selective antagonists were not evaluated since selective antagonists targeting this receptor are not clinically available to patients
The data presented in this study demonstrate that non-selective β-AR antagonists effectively inhibit tumor cell viability and mitogenic signaling in angiosarcomas
Summary
Angiosarcomas are rare vascular tumors of aberrant endothelial histology that exhibit an aggressive and often highly lethal natural course. Inhibition of β-AR signaling by receptor antagonists (beta blockers) has become the gold standard treatment for the benign vascular tumor infantile hemangioma [27, 29], in part through disrupting tumor cell proliferation [30] By translating these findings to malignant angiosarcomas, we showed that propranolol exhibits selective cytotoxicity and tumor suppressive ability against these tumors [21]. Clinical translation of propranolol in combination with chemotherapy drugs has generated overwhelming clinical responses in all reports to date of its use in angiosarcoma patients [31,32,33,34,35,36,37,38]. The clinical effectiveness of propranolol against angiosarcomas recently led to its Orphan Drug Designation by the European Medicines Agency (EMA) for use against soft tissue sarcomas
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