The common antifungal treatment, itraconazole (or ITZ), has shown most promise for prostate, lung and basal cell carcinoma. There are also reports of anticancer effects in leukaemia, ovarian, breast and pancreatic cancer.
“There is lab evidence from cells, there is some in vivo evidence from animal models and we even had some case reports and some clinical trials, but this information was scattered all over and many were unaware of it,” said Pan Pantziarka, a member of the ReDO project and the Anticancer Fund.
Itraconazole is an off-patent triazole widely used in the prevention and systemic treatment of multiple fungal infections, including prophylactic treatment in HIV and immunosuppressed cancer patients.
As an old drug, the study authors suggest it may have multiple molecular targets and be less susceptible to acquired resistance. Also, it could be combined with a range of other drugs, including cytotoxic chemotherapies.
Financial bottleneck
Without licensing for a cancer indication, doctors will be disinclined to prescribe itraconazole; at the same time, there is little financial incentive for those who own the license to take the drug down a new licensing route.
It's a catch-22, according to Lydie Meheus, director of the Anticancer Fund, since only the owners of a market authorization can apply for a new indication.
“We know some companies are looking to tweak the ITZ molecule to make it more bioavailable. By doing this it would be more potent, but it also gives the companies IP protection,” he told in-Pharmatechnologist.com. Mayne Pharma is working on this for basal cell carcinoma.
Two mechanisms of action are noted: it blocks the signal of the Hedgehog pathway, a growth signal pathway targeted by other more cancer drugs, and seems to block angiogenesis too.
This may help point to other cancer types where ITZ may prove beneficial. For instance, the Hedgehog pathway is known to play a role in rare cancers such as SCLC, medulloblastoma or certain types of sarcomas, for which very few new drugs are being developed.
This makes it an interesting candidate for rapid implementation of clinical trials in these diseases with high unmet needs, according to the study authors.
They also suggested a number of drug combinations involving ITZ and standard care in different cancers, such as ITZ and Celecoxib for basal cell carcinoma.
Basal cell carcinoma is treated very well with current drugs, but is difficult to treat once it metastasizes. “There is a range of new and very expensive drugs on the market to treat this, but patients develop resistance very quickly and it appears ITZ acts on a slightly different target to these drugs, so may work to reverse resistance,” said Pantziarka.
ITZ has been around a long time, he adds, so we understand the toxicity and the dosing, in contrast to new drugs. A team at Stanford is planning to assess the combination of ITZ and arsenic trioxide for basal cell carcinoma.
It could be an attractive proposition given the high costs associated with some cancer treatments, such as arbiraterone for prostate cancer, and so could save money for health systems in low and middle income countries.
ReDO has a list of 70 drugs that show potential to be repurposed as anti-cancer agents; the next two it will report on are nitroglycerine, used to treat heart conditions, and diclofenac, a non-steroidal anti-inflammatory drug.