Can new drug approaches elicit a novel dual action of radioiodine treatment?

We are delighted to announce the winner of the Joe Plater BTF Thyroid Cancer Research Award 2021 is Chris McCabe, Professor of Molecular Endocrinology at the University of Birmingham.

His project will look at new drug approaches which can re-sensitise certain forms of thyroid cancer to respond to radioactive iodine (l-131) ablation. The research will look at how future drug approaches could make radioactive iodine treatment more effective by boosting radioiodine uptake and destroying the tumour more effectively and/or lowering radiation doses.

It is hoped this will particularly benefit the estimated 25% of thyroid cancer patients who do not currently respond well to radioactive iodine treatment.

Professor McCabe leads a very successful and active research group and has won BTF Research Awards in 2008 and 2000 to support his ongoing studies into thyroid cancer. He said: ‘I am delighted that the BTF has decided to support this work, and look forward to getting started on our innovative approaches.’

The award has been named after thyroid cancer patient and BTF Patron, Joe Plater, in recognition of his ongoing efforts to raise awareness about thyroid cancer and fundraise for the BTF. Joe commented:

"I am really happy to hear that Professor McCabe's project has been chosen for the award. I think it sounds like a very worthwhile study.  The potential it has to help so many people in a situation similar to myself makes me so proud to have my name associated with it. I look forward to hearing the outcome!"   

Lay summary

The newest data available show us that over a third of a million new cases of thyroid cancer are reported worldwide per year. In general terms, patient outcome is good, but around a quarter of patients do not respond well to the main therapy, which involves the intake of a radioactive isotope (radioiodide 131I). For these patients, life expectancy is significantly reduced. Importantly, around 40,000 people die from thyroid cancer per annum.

Radioiodide is a safe and effective treatment, which has been in clinical use for over 75 years. However, its utilisation has remained largely unchanged since 1942. It is our assertion that new breakthroughs and technologies could transform radioiodide treatment, making it more effective for all patients, but with further significant benefits to those thyroid cancer patients who do not respond well to the therapy.

The radioisotope 131I works by destroying thyroid cells. It is taken up into cells by a transporter protein called the sodium iodide symporter (NIS). This remains a poorly understood protein. For instance, the processes which govern how it reaches the membrane of cells are not understood. We have now pioneered an understanding of the mechanisms which govern the localisation of NIS, and have identified 2 drugs already approved for use in patients elsewhere which enhance its activity.

We now wish to understand whether these 2 drugs have an additional potential benefit in actually making thyroid cancer cells more susceptible to the effects of radiation. We will explore the underlying mechanisms and will seek to challenge our hypothesis that patients might in the future be given a drug, which boosts radioiodine uptake and also confers additional susceptibility to the effects of radiation, meaning more effective tumour destruction and/or lower doses of radiation.

One of the judges commented about the study ‘The identification of candidate drugs and a pathway to ‘resensitise’ thyroid cancer to RAI is an exciting development and this could have real promise for patients with disseminated thyroid cancer who currently have to try TKI/MKI therapy which is never curative.’

Our current project funded via the BTF Joe Plater Award seeks to understand whether these 2 drugs – disulfiram and CB5083 – have an additional potential benefit in actually making thyroid cancer cells more susceptible to the effects of radiation. Our hypothesis is that patients might in the future be given a drug which boosts radioiodine uptake and also confers additional susceptibility to the effects of radiation, meaning more effective tumour destruction and/or lower doses of radiation

In our first full year we have carried out multiple experiments in thyroid cancer cell lines, which on the whole worked extremely well. However, we have recently found that neither drug works in mice to increase radionuclide uptake into the thyroid gland. That is the bad news. The good news is that when we investigated the active metabolite of disulfiram – copper diethyldithiocarbamate, or (Cu(DDC)2) – we found that it did in fact work in mice to enhance radionuclide uptake. We have now tried this via different injection routes, timepoints and doses, all of which are positive. In terms of mechanism, we think that Cu(DDC)2 works at least in part via the same pathway as both disulfiram and CB5083.

In order to best ‘deliver’ the drug in vivo, we set up a new collaboration with a company called Disulfican LTD, who specialise in the nanoencapsulation of drugs like Cu(DDC)2. This ‘protects’ the drug in the bloodstream, allowing it to be more available where it is needed, in this case the thyroid.

Having evolved the research towards a drug which works better in whole organisms, rather than just in cells, we are now about to embark on the second year of studies. We are keen to understand whether Cu(DDC)2 may have a dual role via making cells more sensitive to the effects of radiation, which underpin radioiodine therapy. This is entirely novel research, for which we will return to cancer cell lines in the laboratory. If Cu(DDC)2 does indeed increase the susceptibility of cells to ionising radiation, the good news is that we now know it reaches the thyroid glands of mice at sufficient concentration to increase radioiodide uptake. Thus we will have the best chance of paving the way for future studies in mouse models of thyroid cancer, and, ultimately, human clinical trials. 

Please read the progress report–Jan 2023 for Professor McCabe's study.

You can read more about Professor McCabe’s BTF-funded research at:

BTF Research Award 2008

BTF Research Award 2000

Tribute to BTF patron, Joe Plater