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Exploring beta-blocker propranolol in angiosarcoma treatment

Propranolol in clinical trial angiosarcoma

Brussels - A recent clinical trial investigated propranolol, commonly used for high blood pressure, as a potential treatment for angiosarcoma, a rare and aggressive cancer. Funded by the Anticancer Fund, the study explored whether propranolol could help control tumour growth before traditional treatments start, aiming to increase the chances of survival. 

Angiosarcoma is an aggressive and rare type of cancer that develops from the blood vessels. The standard treatment for angiosarcoma that has not spread, is to surgically remove the entire tumour, sometimes in combination with radiation. However, despite optimal disease management, in approximately half of patients the tumour returns. This is because angiosarcoma carries a high risk of spreading to other parts of the body, and some tumour cells may have already began spreading, unnoticed, before the tumour was removed. 

By improving the neoadjuvant treatment (i.e. treatment before the ‘main’ treatment; usually surgery) and thereby effectively treating micro-metastases at an early stage, the risk of relapses might be reduced, potentially leading to higher survival rates.

New drugs for this setting of angiosarcoma treatment are therefore urgently needed. 

A high-blood pressure medicine to treat cancer? 

Researchers have identified propranolol, a drug commonly used to treat high blood pressure, as a potential treatment option for angiosarcoma. Besides its original purpose, beta-blocker propranolol showed promising anti-tumour effects in laboratory studies and case reports and has already been effectively repurposed to treat another type of blood vessel tumour in children (infantile haemangioma). 

Orphan Drug Designation for angiosarcoma 

This led to the Anticancer Fund successfully obtaining an orphan drug designation by the European Medicines Agency (EMA) for propranolol in 2016. Orphan drug designation is a special status granted by regulatory agencies such as the EMA to drugs intended to treat rare diseases or conditions, in this case angiosarcoma - while it was originally developed and approved for a different purpose. The orphan drug designation of propranolol for angiosarcoma offers various benefits, such as optimised regulatory processes and assistance with clinical trial design, to encourage further investigation of the drug's potential for treating angiosarcoma. 

Can propranolol modify angiosarcoma tumours? 

The Anticancer Fund collaborated with researchers from the Netherlands Cancer Institute (NKI) to initiate a so-called ‘window of opportunity’ trial, which aimed to prove the concept that propranolol alone could modify angiosarcoma tumours.  

A window of opportunity trial is a clinical study that aims to investigate the effects of a treatment during a specific period of time, in this case before standard treatment begins, where there is a waiting period before standard treatment is given – the ‘window’.  

The aim of this trial was to evaluate the anti-tumour activity of propranolol in patients with angiosarcoma before proceeding to standard treatment. In the trial, angiosarcoma patients received propranolol for 3 to 6 weeks. 

What have we learned? 

This trial did not show persuasive anti-tumour activity after treatment with propranolol in angiosarcoma patients – in only 2 out of 14 patients the tumour regressed. Several factors might have affected the result of this trial. First of all, it is unclear whether the total duration of propranolol treatment in this trial was long enough, and whether the total dose of propranolol was sufficient to achieve the wanted effect. Most patients could not get to the highest dose because propranolol made their heart rate slow down too much at lower doses already. Furthermore, it remains unclear what exactly made the tumour respond to the treatment in two patients but not in the others. 

"Unfortunately, a short course of propranolol did not change the course of disease for patients with angiosarcoma. However, with tremendous efforts of all the patients and researchers involved, we did gain a lot of new knowledge on this incredibly rare disease."
Dr. Neeltje Steegs, Principal Investigator, NKI, The Netherlands 

What’s next? 

Further trials are needed to better understand the anti-tumour effects of propranolol. In these future trials, a longer treatment duration should be considered to find out which patients might actually benefit from treatment with the beta-blocker. In addition, there are indications that combining propranolol with immunotherapy could be of added value in the treatment for angiosarcoma - though a direct effect of propranolol on the immune cells could not be confirmed in this trial. Currently, the effect of propranolol in combination with immunotherapy is being investigated in a clinical trial in patients with metastatic angiosarcoma in Denmark. 

"With a limited clinical activity that is independent of the beta-adrenergic receptors, it’s hard to argue that propranolol alone should be given another chance in angiosarcoma. A much better next step would be to run a trial of propranolol combined with metronomic chemotherapy (methotrexate and vinblastine), as developed at the Tata Memorial Centre in Mumbai, India, where 4 out of 7 angiosarcoma patients had a very good tumour response."
Prof. Nicolas André, Professor Paediatric Oncology, La Timone University Hospital, France 

The Anticancer Fund will keep a close eye on the future research on this topic and will keep looking for new treatment options for angiosarcoma patients, as new drugs are urgently needed.