Targeting Angiosarcoma Vascular and Metabolic Signaling by Blocking Beta Adrenergic Receptor Signaling

Angiosarcomas are highly lethal tumors composed primarily of aberrant lymphatic and/or vascular endothelial cells. These tumors most commonly occur as facial dermatologic lesions and account for over 50% of radiation-induced sarcomas following breast cancer therapy. The five year survival rate of angiosarcoma patients is less than 30%, and even the addition of novel molecularly-targeting therapies has shown a minimal to absent response. Very little therapeutic progress has been made over the past several decades to improve treatment outcomes, thus effective therapeutics against this disease are desperately needed. Preliminary data from our lab indicate that blocking beta adrenergic receptor (ADRB) signaling disrupts angiosarcoma tumor cell survival, inhibits xenograft angiosarcoma tumor progression, and reduces proliferation of tumor cells in patients with angiosarcoma. While ADRB antagonists such as generic beta blockers have been used for decades on patients with cardiovascular disorders with minimal side effects, the mechanism by which these drugs preferentially target angiosarcomas while sparing normal endothelial cells is not known. Our data suggest that ADRB antagonism disrupts angiogenic signaling by blocking vascular cascades important for newly developing vessels and tumor vasculature. Our results also suggest that angiosarcomas rewire their metabolism to support the high metabolic demands of oncogenic growth, and that ADRB antagonism disrupts this critical process. Therefore, we hypothesize that ADRB antagonists preferentially block angiosarcoma tumor growth through targeting aberrant angiogenic and metabolic processes, exploited by the tumors for their own growth advantage. We will test our hypothesis through the following two objectives:

1. Identify aberrant angiogenic signatures in angiosarcomas and understand how ADRB antagonism selectively targets their vascular and lymphatic networks.

2. Elucidate the pro-angiogenic metabolic signaling pathways used by angiosarcomas and determine how ADRB antagonism selectively targets these networks.

Upon completion of this project, we will understand how vascular and lymphatic angiogenic processes as well as cellular metabolism are deregulated in angiosarcomas, how ADRB signaling contributes to these processes, and how inhibition of ADRB activity preferentially disrupts these processes for therapeutic gain. Our approach is novel in that it seeks to understand the mechanism by which a 60-year old class of FDA approved generic drugs is capable of preferentially inhibiting an exceptionally chemoresistant and highly metastatic vascular sarcoma with an abysmal survival rate.