Targeting the sarcoma tumor microenvironment using adrenergic receptor antagonists

Vascular sarcomas (e.g. angiosarcomas, hemangiosarcomas, and hemangioendotheliomas) represent a therapeutic challenge since new treatment approaches have not occurred in several decades. We and others recently published reports showing a remarkable 100% response rate (complete and partial responses) of angiosarcoma patients to the beta adrenergic receptor (beta-AR) antagonist propranolol. The clinical effectiveness of propranolol against angiosarcomas has led to Orphan Drug Designation for propranolol in the EU and accelerated approval in the US for the treatment of soft tissue sarcomas.Although all patients demonstrated durable responses versus standard-of-care approaches, disease progression eventually occurred.

Based these outcomes, we pursued mechanisms of sarcoma resistance to propranolol. We found that cholesterol processing may be essential for sarcoma cell viability and that alpha- and beta-AR antagonists disrupt these processes. Furthermore, alpha-AR antagonists are superior in reducing sarcoma cell viability compared to propranolol, and sarcoma cells upregulate alpha-ARs in response to propranolol exposure. Our results suggest that sarcomas increase the expression of alpha-ARs to reestablish cholesterol homeostasis and circumvent beta blockade. We hypothesize that alpha-AR antagonists will provide a more efficacious approach to therapy by targeting cholesterol pathways essential for tumor cell viability and by disrupting communication within the tumor microenvironment. We will investigate our hypothesis by developing two independent, yet complimentary, specific aims.

Aim 1: Determine the therapeutic potential of adrenergic antagonists alone and in combination with chemotherapy.
Hypothesis: Alpha- or alpha/beta-AR antagonists will provide superior inhibition of tumor growth over propranolol in a tumor xenograft model. Inhibition of tumor growth will be further enhanced by combining with chemotherapy.

Aim 2: Identify the metabolic mechanisms through which adrenergic antagonists block tumorigenesis and alter signaling patterns within the TME.
Hypothesis: Adrenergic antagonists will reduce cholesterol uptake and processing by tumor cells, leading to altered signaling and metabolic patterns within the TME.

Aim 1: The effects of propranolol and an alpha or alpha/beta antagonist will be compared to determine if alpha-AR antagonists are superior to propranolol for inhibiting tumor growth. The therapeutic effects of antagonists in combination with chemotherapy will also be determined. Aim 2: We will use a genomics approach (RNA-Seq) to identify mechanisms of sensitivity and resistance of sarcoma and tumor stroma cells in response AR antagonists. Upon completion of this project, we expect to gain an understanding of the mechanistic development of resistance to propranolol and determine if treating angiosarcoma patients with alpha/beta- or alpha-targeting antagonists will further advance patient outcomes.