We and others have recently reported the therapeutic benefit

We and others have recently reported the therapeutic benefits of propranolol in 2 patients with relapsing metastatic and multi-focal angiosarcoma, respectively (Banavali et al., 2015; Chow et al., 2015). Here, we extended these initial findings to 7 consecutive angiosarcoma patients with dismal prognosis. Treatment protocol design was based on the synergistic interaction of propranolol and vinblastine observed in vitro. In addition, methotrexate was included based on its anti-inflammatory properties and previous report of efficacy of low-dose methotrexate in combination with vinblastine against other forms of aggressive soft-tissue tumors, like inoperable fibromatosis (Azzarelli et al., 2001). The 100% response rate based on RECIST criteria and extended PFS and OS reported here are impressive given the advanced disease stage in all 7 patients and the common drug refractoriness of angiosarcomas (Young et al., 2010). We tested 3 patient tumors for β-adrenergic receptor gene expression by RT-PCR and found that all 3 tumors expressed ADRB1 at similar levels while ADRB2 expression was more variable and barely detectable in 2 out of 3 patients. This is somewhat different from the results of tissue microarray immunostaining experiments that reported high ADRB2 expression in various vascular tumors, including angiosarcoma (Chisholm et al., 2012; Stiles et al., 2013). It is however important to note that Phos-tag Biotin directed towards G-protein coupled receptors notoriously lack specificity (Michel et al., 2009) and gene expression analysis may provide more reliable results than immunostaining of tumor sections. Elsewhere, stress-induced tumor growth, angiogenesis, metastasis and resistance to treatment has been directly linked to ADRB2 signaling (Cole and Sood, 2012). Future studies will need to address the contribution of the different adrenergic receptors in the synergism between propranolol and chemotherapy agents in angiosarcoma and other refractory tumors, such as triple-negative breast cancer and neuroblastoma (Pasquier et al., 2011; Pasquier et al., 2013). Our study has a number of caveats that should not be ignored. First, this is an unpowered clinical study with a mixture of first line and relapse treatments. Secondly, treatment was slightly heterogeneous. For instance, Patients #3, #4, and #7 who had multiple bone metastases and were in pain at presentation, also received celecoxib 200mg PO bid and weekly zoledronic acid 1mg IV for the first 3months of therapy. In addition, given the palliative nature of treatment, the dose of chemotherapy agents was decreased in the presence of grade II toxicities, in order to prevent the occurrence of grade III and IV toxicities. This heterogeneity in terms of clinical setting and treatment protocol does not allow rigorous comparison with historical controls. Finally, our study did not include the use of propranolol as monotherapy to demonstrate its potential anti-tumor activity, although recent in vivo data (Stiles et al., 2013) and a clinical case report (Chow et al., 2015) suggest it may also prove useful as a single agent. It is however important to note that previous studies reported positive results with the use of metronomic chemotherapy to treat malignant vascular tumors (Vogt et al., 2003; Mir et al., 2011), thus providing further rationale for our combination treatment.
Conclusions Drug repositioning provides a unique opportunity to develop new treatment modalities that can be rapidly translated into the clinic. This approach is particularly attractive for low- and middle-income countries (LMIC), where the latest drugs and therapies developed in high-income countries (HIC) are unaffordable for the wide majority of patients (André et al., 2013). Here, despite the limitations of our study we produce strong evidence for the repositioning of β-adrenergic receptor antagonist, propranolol, in combination with vinblastine-based metronomic chemotherapy for the treatment of advanced angiosarcoma. The safety and efficacy of this treatment will now need to be further validated in a larger phase I/II clinical trial. Importantly, this type of treatment comes at a fraction of the cost of experimental treatments developed for angiosarcoma patients in HIC and it can be administered on an out-patient basis with manageable toxicities. It thus represents a very promising and economically viable strategy for patients living in LMIC, thus paving the way for the development of a fair, global oncology.