- Drugs, such as Vismodegib, are often only partly or temporarily helpful in Gorlin Syndrome
has been used for many years to treat fungal infections.
- For this reason, Itraconazole is cheap and we know about the side effects.
- Test tube experiments show Itraconazole is effective in treating BCC cells and works in a different way from Vismodegib.
- Clinical trials of Itraconazole only show partial success so far, possibly because it is difficult to get Itraconazole into the blood stream.
- Modified versions of Itraconazole are being tested.
Why we need more medications
Hedgehog pathway inhibitors are already licensed or being researched for use in Gorlin Syndrome, but are not 100% effective. For example, Vismodegib treatment does not shrink all tumours a person with Gorlin Syndrome will have. Sometimes, Vismodegib only shrinks the tumours for a few months, then they start growing again. This may be because the tumour cells mutate and the drugs no longer affect them, very much like bacteria can become resistant to antibiotics. So, Vismodegib is not 100% effective. For this reason, the search for effective treatments continues.
What do we know about Itraconazole?
Itraconazole is a drug taken by mouth which has been available for many years. It was originally developed for fungal infections. Even though is effective for fungal infections, some people have had to take it for many weeks or months. Because of this experience of long-term Itraconazole, we already know a lot about the potential problems it can cause.
These problems include:
-Itraconazole is absorbed quite quickly from the gut into the blood, but only about 50% of a dose is absorbed. Even less is absorbed if the person taking it is also taking some ulcer medications.
-It can interfere with other medications, for example, treatments for epilepsy. These ‘drug interactions’ can be two – way. The interactions can prevent the Itraconazole from working or prevent the other drug from working (for example causing convulsions in people taking medication for epilepsy).
-It can cause liver damage. For this reason, people taking it for weeks or months should have blood tests to check their livers have not been affected.
On the other hand, a huge advantage of Itraconazole may be that it is very cheap. Drugs which have been around for many years lose their patent. This means that many different manufacturers can start producing the drug and prices fall.
In theory, does Itraconazole work in Gorlin Syndrome?
The pharmaceutical industry is always searching for new anti-cancer drugs and will very often do test tube experiments on existing drugs to see if they work in cancer. This is what happened with Itraconazole, which was found to block the hedgehog pathway.
In test tube experiments, Itraconazole was found to block a different part of the sonic hedgehog pathway from drugs such as Vismodegib. Both drugs affect a different part of a molecule called ‘smoothened’. This means there is potential for combining these drugs. This could help reduce the risk of cancerous cells becoming resistant to either drug. It could also help ‘rescue’ people who have become resistant already, for example as a result of being on Vismodegib for many months.
Needless to say, these theoretical benefits from Itraconazole have each needed to be tested in carefully designed clinical trials.
Has Itraconazole been shown to work for BCCs?
At least one study has shown that Itraconazole, given by mouth can reduce the size of BCCs over several months. This study did not show the expected benefit for people for whom Vismodegib had stopped working because of acquired resistance to Vismodegib1.
It is important to understand that there were no people with Gorlin Syndrome in this trial. Also, there was no placebo or randomisation and the trial only continued for a short time. Not all other trials looking at the effects of Itraconazole on BCCs have failed to show consistent benefits. For these reasons, it is probably unwise to rely on Itraconazole as the only treatment for BCCs in Gorlin Syndrome.
Are alternative forms of Itraconazole being tested?
Yes –various ways of improving Itraconazole are being tested:
Itraconazole can be combined with a substance (called a polymer) to even-out the way it is absorbed from the gut. This means, for example, that Itraconazole should behave more predictably and, hopefully, cause fewer side effects. One example of this kind of approach is SUBA – Itraconazole, which may well be tested in Gorlin Syndrome over the next few months.
A second alternative is to use two drugs at once – Itraconazole and a different drug. Researchers have found that combining Itraconazole with a safe form of arsenic was effective in treating BCCs in people for whom Vismodegib had stopped working2. This was a very small trial and further research is underway to evaluate this combination.
A third approach has been to put Itraconazole in a gel, which is then applied to the BCC. A small trial of Itraconazole gel was completed in 20183 and early results showed that the Itraconazole did get into the BCCs, but did not reach the blood stream. Unfortunately, the trial did not show any benefits of the Itraconazole gel compared to the placebo gel which was used in parallel. This could be because the trial was too short (it lasted 12 weeks) or because Itraconazole just doesn’t work.
Where do we go from here?
Itraconazole seems to be effective in treating BCCs, although it may need to be tweaked to get the best benefits. More research is needed. Regular Itraconazole capsules are not likely to be interesting for pharmaceutical companies to investigate. A tweaked Itraconazole (for example the gel or SUBA Itraconazole) are much more likely to be trialled over the next few years.
Hedgehog pathway – a process inside cells, which stop them growing too rapidly
PTCH1 – a gene which controls one part of the hedgehog pathway.
Smoothened – a molecule in the hedgehog pathway
Vismodegib – inhibits the hedgehog pathway, being used in Gorlin Syndrome
Itraconazole – drug used to treat fungal infection. May be helpful in Gorlin Syndrome.
Where can I read more about Itraconazole and Gorlin Syndrome
1 Kim DJ et al, Open Label Exploratory Phase II Trial of Oral Itraconazole for The Treatment of Basal Cell Carcinoma. Journal of Clinical Oncology, 2014
2 Ally MS, Effects of Combined Treatment with Arsenic Trioxide and Itraconazole in Patients with Refractory Metastatic Basal Cell Carcinoma. Journal of the American Medical Association Dermatology 2016
3 Kim GE, Pilot study of topical Itraconazole for the treatment of basal cell carcinomas in gorlin syndrome patients, Journal of Investigative Dermatology 2018