Non-selective beta blockers inhibit angiosarcoma cell viability and increase progression free- and overall-survival in patients diagnosed with metastatic angiosarcoma

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.

Regression of primary cardiac angiosarcoma and metastatic nodules following propranolol as a single agent treatment

“…The targets of propranolol, the beta adrenergic receptor proteins (β-AR1, β-AR2, β-AR3), are expressed in angiosarcoma [ 25 , 27 ]. Preclinical studies using in vitro and in vivo angiosarcoma models indicate that propranolol as a single agent is capable of reducing tumor cell proliferation, selectively inducing tumor cell apoptosis while sparing non-diseased cell types, and inhibiting the growth of angiosarcoma xenografts in animal tumor models [ 23 , 25 , 26 ]. Translation of these findings into human patients revealed that propranolol alone is capable of reducing the angiosarcoma proliferative index after only 1 week of treatment [ 20 ], however the long term efficacy of propranolol as a single agent therapy was not individually evaluated in the aforementioned study, as the tumor was subsequently treated with radiation and chemotherapy.…”

“…Translation of these findings into human patients revealed that propranolol alone is capable of reducing the angiosarcoma proliferative index after only 1 week of treatment [ 20 ], however the long term efficacy of propranolol as a single agent therapy was not individually evaluated in the aforementioned study, as the tumor was subsequently treated with radiation and chemotherapy. Non-randomized prospective and retrospective studies have combined propranolol with conventional anti-sarcoma therapies, leading to substantially increased progression free- and overall-survival of angiosarcoma patients [ 23 , 26 ], however randomized clinical studies are necessary to comprehensively evaluate the efficacy and optimal dosing of propranolol against angiosarcoma. Several targeted therapeutics such as Pazopanib, TRC105, and others are currently being tested clinically against this tumor type.…”

“…Emerging evidence from a number of retrospective clinical analyses and prospective case reports indicates that the beta blocker propranolol exhibits clinical efficacy against primary and metastatic angiosarcomas [ 19 - 26 ]. Due to a dearth of effective treatment options against angiosarcomas, and the remarkable clinical outcomes reported in the literature for propranolol, this beta blocker has recently received Orphan Drug Designation against angiosarcomas by the European Medicines Agency.…”

Drug Repurposing of β-blocker Propranolol in Osteosarcoma: Preclinical Antitumor Efficacy Alone or in Combination with Chemotherapy.

“…Moreover, PPN demonstrated to reverse protumoral effects mediated by stress hormones in chronic or surgical stress models, reducing angiogenesis and metastasis, and increasing immune function [10,15]. Taking all these data into account, assessment of PPN anticancer properties has recently reached clinical stages for angiosarcoma, ovarian cancer and melanoma, mainly as a surgical adjuvant or in combination with chemotherapy or biologic targeted therapy [16][17][18]. Despite sympathetic nervous system (SNS) activation and signaling pathways triggered by catecholamines such as epinephrine and norepinephrine are deeply involved in cancer initiation and progression [19,20], little is known about the speci c role of catecholamines or β-AR signaling in OSA.…”

PropAngio study protocol: a neoadjuvant trial on the efficacy of propranolol monotherapy in cutaneous angiosarcoma—a proof of principle study

“…11 12 The pharmacological effects of propranolol in infantile haemangioma are presumed to cause vasoconstriction, a decreased expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, inhibition of migration and proliferation of tumour cells and induction of apoptosis of endothelial cells. [12][13][14][15][16] Angiosarcoma have several similarities with infantile haemangioma, including its high β-adrenergic receptor expression and the suggested important role of VEGF in malignant growth. 14 17 18 Several small case reports and case series have confirmed the idea that propranolol could be repurposed to treat angiosarcoma.…”