Abstract
Background Drug repurposing can speed up access to new therapeutic options for cancer patients. With more than 2000 drugs approved worldwide and 6 relevant targets per drug on average, the potential is quantitatively important. In this paper, we have attempted to quantify the number of non-cancer drugs supported by either preclinical or clinical cancer data.
Methods A PubMed search was performed to identify non-cancer drugs which could be repurposed in one or more cancer types. Drugs needed at least one peer-reviewed article showing an anticancer effect in vitro, in vivo or in humans.
Results A total of 235 eligible non-cancer drugs were identified (Table 1). Main charateirstics of the drugs are summarized in Table 2. 67 (29%) are on the WHO list of essential medicines and 176 (75%) are off-patent. 133 (57%) had human data in cancer patient(s). Four were listed in clinical guidelines, namely thalidomide, all-trans retinoic acid, zoledronic acid and non-steroidal anti-inflammatory drugs (NSAID). Several drugs have shown a survival benefit in randomized trials such as cimetidine (colorectal cancer), progesterone (breast cancer) or itraconazole (lung cancer). Several other drugs induced responses in rare tumours, like clarithromycin, timolol or propranolol.
Conclusion We have found that the number of off-patent repurposing opportunities is large and increasing. Joint non-commercial clinical development (academics, governments, charities) may bring new therapeutic options to patients at low cost, especially in indications for which the industry has no incentive to invest in.
Introduction
Drug repurposing can speed up access to new therapeutic options for cancer patients. Whereas it is not unusual to attempt to find new cancer uses for existing anticancer drugs, less attention and efforts are made to find anticancer uses of non-cancer drugs 1. However, many non-cancer drugs could be potentially repurposed against cancer though to our knowledge no figures have been put forward so far 2. One advantage of non-cancer drugs is that they represent a way to adapt to new knowledge about cancer. For instance, Tadalafil (PDE-5 inhibitor, erectile dysfunction), inhibits myeloid-derived suppressor cells (MDSC) in cancer patients 3. Or propranolol (beta-blocker, hypertension) reduces proliferation and migration of angiosarcoma models 4,5, by blocking beta-adrenergic receptors expressed by angiosarcoma cells 6.
With more than 2000 drugs approved worldwide and 6 relevant targets per drug on average 7, the potential is quantitatively important. What’s more, with regular new drug approvals, the toolbox that repurposed drugs represent is growing every year. Even antibodies are now being repurposed (e.g. rituximab in pemphigus 8), sometimes based on the discovery of off-target effects 9,10.
When a drug loses its patent protection, the incentives for the market authorization holder are also lost. Sometimes, other private entities attempt to protect the new therapeutic use by various means and undertake a commercial development11. However, this strategy remains financially risky, which makes it less attractive to investors and venture capitalists compared to other biotech investments. We have called these drugs “financial orphan drugs” 12.
In this paper, we have attempted to quantify the number of non-cancer drugs supported by either preclinical or clinical cancer data.
Methods
A PubMed search was performed to identify non-cancer drugs which could be repurposed in one or more cancer types. Drugs needed at least one peer-reviewed article showing an anticancer effect in vitro, in vivo or in humans.
Results
A total of 235 eligible non-cancer drugs were identified (Table 1). Main characteristics of the drugs are summarized in Table 2. 67 (29%) are on the WHO list of essential medicines and 176 (75%) are off-patent. 133 (57%) had human data in cancer patient(s). Four were listed in clinical guidelines, namely thalidomide, all-trans retinoic acid, zoledronic acid and non-steroidal anti-inflammatory drugs (NSAID). In the first 3 cases, pharmaceutical companies took the lead and re-branded or re-formulated the drugs. This was not the case for NSAIDs, listed in desmoid tumours guidelines and used off-label.
Several drugs have shown a survival benefit in randomized trials such as cimetidine (colorectal cancer) 13, progesterone (breast cancer) 14 or itraconazole (lung cancer)15. Of note, several other drugs induced responses in rare tumours, like clarithromycin 16, timolol 17,18 or propranolol 19–22.
Discussion
We have found that the number of off-patent repurposing opportunities is large and increasing.
Until now, practice-changing examples have been limited despite the evidence. Joint non-commercial clinical development (academics, governments, charities) may bring new therapeutic options to patients at low cost, especially in indications for which the industry has no incentive to invest in. This may relieve healthcare systems currently under high financial stress.
A change in market authorisation regulation will be required to avoid off-label use. The Anticancer Fund is actively pursuing this innovative strategy, as exemplified by the granting of an EMA orphan designation for propranolol in angiosarcoma.