Propranolol for melanoma

Australia has the highest rate of skin cancer and melanoma in the world, but studies have found that non-cardio selective beta-blockers such as propranolol exhibit anti-tumour effects.

Before the age of 70 years, at least 2 in 3 Australians will be diagnosed with skin cancer. Melanomas are much less common (2% of all skin cancers), but more deadly, being responsible for 75% of all skin cancer-related deaths.

Melanomas are the third most commonly diagnosed cancer – after prostate and bowel cancer for males, and breast and bowel cancer in females.

Many people think skin cancers are only found in older people who spend a lot of time in the sun. However, younger people, and those who never spend time in the sun can also develop sun cancers.

For now, being sun smart, and getting regular skin checks to identify changes to the skin to allow for early treatment are the main options for preventing melanomas and skin cancers.

For people with early stages of melanoma, surgical removal is often the only treatment that is required. Lymph nodes nearby may also be removed to help prevent the melanoma from spreading.

For later stages of melanoma, radiation therapy, chemotherapy and immunotherapy (ipilimumab and pembrolizumab, which trigger the body’s immune system) may be required.

Targeted therapy is also used for patients with speci­fic gene mutations identi­fied to be involved with melanoma development. As with all cancers, melanomas can recur after the original cancer is removed.

An interesting find

In recent years, retrospective studies found people taking beta-blockers for other conditions had better outcomes with regards to melanoma progression than those not taking beta-blockers. Further work revealed this was not a class effect – it was in fact the non-cardio selective beta-blockers such as propranolol that exhibited the anti-tumour effects.

Non-selective beta-blockers work by competitively blocking beta-adrenergic receptors in the heart, peripheral vasculature, bronchi, pancreas, uterus, kidney, brain and liver. In particular, propranolol not only blocks beta1- and beta2-receptors, but also the serotonergic 5HT1a and 5HT1b receptors, and sodium voltage-gated channels NaV.

So, how does all this help with tumours? Keratinocytes and melanocytes produce noradrenaline (as an autocrine or paracrine hormone) that affects skin cells. This noradrenaline is thought to cause melanoma cells to release pro-tumorigenic and pro-angiogenic factors that cause tumour growth and invasion. In vitro and in vivo work on mice found propranolol inhibited growth of human melanoma cells.

More recently, a cohort study investigated if propranolol improved progression-free survival in people with melanoma (stage IB to IIIA) with no evidence of metastasis. At 3 years, taking 80 mg propranolol daily (n = 19), compared to a placebo (n = 34) from the time of diagnosis saw an 80% risk reduction for recurrence from propranolol hazard ratio 0.18; 95% con­fidence interval 0.04-0.89; p = 0.03).

There was also a trend toward increased overall survival (hazard ratio 0.64; 95% con­fidence interval 0.10-3.96; p = 0.63), but the short follow-up duration limited the power of the study.

Conclusion

Trials with larger numbers of participants, followed for longer periods of time are certainly required to examine the clinical utility of propranolol for melanoma.

Nevertheless, this is an exciting first step toward repurposing a cheap, well tolerated, and easily available medication for preventing melanomas.

Table 1. Propranolol dosing information

* Propranolol does not have an indication for this condition – dose provided is indicative only. References: Australian Medicines Handbook

The PSA clinical evidence brief on melanoma is available here.

References

1. De Giorgi V, Grazzini M, Benemei S, et al. Propranolol for off -label treatment of patients with melanoma: results from a cohort study. JAMA Oncol 2018 Feb 8;4(2):e172908.
2. Wrobel LJ, Le Gal FA. Inhibition of human melanoma growth by a non-cardioselective ß-blocker. J Invest Dermatol 2015 Feb;135(2):525-31.