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

The winner of the Joe Plater BTF Thyroid Cancer Research Award 2021 was Chris McCabe, Professor of Molecular Endocrinology at the University of Birmingham.

His project looked at new drug approaches which can re-sensitise certain forms of thyroid cancer to respond to radioactive iodine (l-131) ablation. The research looked 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. At the time of winning the Award 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, who sadly died in 2023. The Award was made in recognition of his efforts to raise awareness about thyroid cancer and fundraise for the BTF. At the time, 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!"   

Final report on study

What was the background to your study?

Beta-emitting radioiodide (¹³¹I) therapy has been utilised for over 75 years to safely destroy remaining thyroid cancer cells after surgery and to target metastases. The sodium iodide symporter (NIS) is the sole transporter of iodide into human cells. The ability of NIS to uptake radioiodide is diminished in 25-50% of thyroid cancer patients, due to reduced expression and mislocalisation away from the plasma membrane of cancer cells, its only site of transport activity. Understanding and manipulating how NIS moves to the membrane of cancer cells  is now essential to enhance the function of NIS in radioiodide treatment, and thereby address the ~40,000 lives lost worldwide to aggressive thyroid cancer per annum.

What was the aim of your research?

We previously identified a protein called VCP as a pivotal protein in the movement of NIS within cancer cells (Fletcher AL et al Cancer Research 2020). When we looked at the ability of 1,200 different drugs to increase radioiodide uptake (Read ML et al Cell Chemical Biology 2022), we found that 6 of these inhibit activity of VCP, whilst an additional drug called disulfiram inhibited a protein which binds to VCP called NPL4  

This project aimed to understand several things about how VCP and NPL4 control the ability of the transport protein NIS to take up radioactive iodine into thyroid cancer cells, with the aim of designing drug approaches to increase the killing of tumour cells in patients with thyroid cancer. 

Were there any patients involved in your research?

No patients were involved, but our work is of direct relevance to patients with aggressive thyroid cancer which does not respond well to radioiodine treatment.

How did you conduct the research?

We carried out laboratory experiments in human thyroid cancer cell lines, as well as experiments in mice. In scientific terms, we used RNA-Seq and TaqMan RTPCR to identify Cu(DDC)2-regulated transcriptional pathways. NIS function was monitored in wild-type BALB/c mice via Technetium-99m pertechnetate (99mTc) uptake following intravenous administration.  Thus we used a range of scientific approaches following our initial NanoBiT, siRNA knockdown, radioiodide uptake and proteasomal assays.

What were your findings?

Our drugs which target VCP in thyroid cancer cells turned out to regulate proteins which themselves control how other critical proteins are switched on and off. This gave us new insight, because our initial observation was that drugs which inhibited VCP (and therefore increased radioactive iodide uptake into thyroid cancer cells) did so by changing its ability to alter protein structure. In essence then, we found a drug which has a double action in thyroid cancer cells, increasing radioactive iodide uptake by two different mechanisms. When we tested this in mice, we discovered that this drug increased how much radioactivity accumulated in their thyroid glands. We have now followed this up in a mouse model of human breast cancer, where the drug also works.

What role did the BTF funding play?

BTF funding was instrumental in getting this project up and running and allowing us to increase our mouse model numbers. This was a classic example of taking very fundamental findings and moving them closer to patient utility. We have to use mice so that we can appraise the ability of our strategies to work in a whole animal setting. But these experiments have shown us that we can in fact enhance the amount of radioactivity we target to the thyroid gland by changing the function of VCP.

What are the next steps in your research?

We have recently moved this into breast tumour work, and demonstrated consistent findings. It has long been suggested that radioiodine therapy could be used in patients with breast cancer. Our preliminary findings are very encouraging, and we will now broaden these experiments. At the same time we are testing the same drugs from this BTF project in a mouse model of aggressive thyroid cancer, taking us closer still to patient treatment than our existing experiments in normal mice. 

Previous research updates from Prof McCabe

Lay summary 2021

Progress report–Jan 2023

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

BTF Research Award 2008

BTF Research Award 2000

Tribute to BTF patron, Joe Plater

Read about past BTF Research Award-funded studies

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