TRANSFORMING CELLULAR IMAGING AND ABLATION STRATEGIES VIA NEW MECHANISTIC UNDERSTANDING OF THE SODIUM IODIDE SYMPORTER
Lead Research Organisation:
University of Birmingham
Department Name: Inst of Metabolism & Systems Research
Abstract
There are many ways to image inside the human body, but arguably the most sensitive method relies on the uptake of tracer amounts of radioactive substances, which can be quantified by whole body scanners. The detection of key radioactive substances such as iodide relies on the function of a transporter protein, which needs to be in the membranes of cells so that it can act as a kind of pore. The transporter protein NIS is responsible for getting radioactive iodide and related substances inside cells. In addition to imaging, NIS is used to destroy tumours - especially those from the thyroid - and even where the tumour has spread around the body.
One critical problem is that NIS is not always located at the outer membrane of cells where it acts as a pore, making the detection of radioiodide less sensitive than it would otherwise be. Our work is focussed on finding new ways of regulating NIS with drugs, so that we can actively target it to the membrane of cells in patients. Together with world-leading experts we will carry out extensive first-of-its-kind drug screening to identify new drug strategies, to understand how they work, and then to apply them. This has the potential to improve thyroid cancer imaging and treatment, to effect a new therapy for breast cancer, and to enhance the many other experimental and pre-clinical settings in which NIS is currently used.
Clinically, 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 third of patients do not respond well to the destruction of thyroid tumours with radioactive iodide. This is particularly a problem where patients have metastases. It is not currently well understood how NIS behaves in metastatic disease. But for patients in whom NIS is not working well, life expectancy is significantly reduced, and around 45,000 people die from thyroid cancer per annum.
Interestingly, NIS expression becomes 'switched on' in ~80% of breast tumours, including aggressive triple-negative breast cancers and their metastases. Radioiodide treatment of breast cancer has several attractive clinical features, but while radioiodide uptake into breast tumours and metastases has been demonstrated, levels of uptake are not sufficient to achieve a therapeutic effect. This is because NIS is generally found in a non-functional intracellular location, away from the cell membrane.
Radioiodide is a safe and effective modality which has been in clinical use for over 80 years. However, its utilisation has remained largely unchanged since 1942. 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. However, our work goes beyond this. We wish to pioneer new understanding into the regulation of NIS so that we can apply this to a number of different settings. For instance, via collaborators we will also apply our findings to models of NIS gene delivery and tumour spreading. We hope our work will inform the research of colleagues around the world who already exploit NIS function in multiple settings, adding new insight to these approaches. This ambitious programme of work will therefore use cutting edge approaches to solve the problem of systemically inducing NIS function.
One critical problem is that NIS is not always located at the outer membrane of cells where it acts as a pore, making the detection of radioiodide less sensitive than it would otherwise be. Our work is focussed on finding new ways of regulating NIS with drugs, so that we can actively target it to the membrane of cells in patients. Together with world-leading experts we will carry out extensive first-of-its-kind drug screening to identify new drug strategies, to understand how they work, and then to apply them. This has the potential to improve thyroid cancer imaging and treatment, to effect a new therapy for breast cancer, and to enhance the many other experimental and pre-clinical settings in which NIS is currently used.
Clinically, 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 third of patients do not respond well to the destruction of thyroid tumours with radioactive iodide. This is particularly a problem where patients have metastases. It is not currently well understood how NIS behaves in metastatic disease. But for patients in whom NIS is not working well, life expectancy is significantly reduced, and around 45,000 people die from thyroid cancer per annum.
Interestingly, NIS expression becomes 'switched on' in ~80% of breast tumours, including aggressive triple-negative breast cancers and their metastases. Radioiodide treatment of breast cancer has several attractive clinical features, but while radioiodide uptake into breast tumours and metastases has been demonstrated, levels of uptake are not sufficient to achieve a therapeutic effect. This is because NIS is generally found in a non-functional intracellular location, away from the cell membrane.
Radioiodide is a safe and effective modality which has been in clinical use for over 80 years. However, its utilisation has remained largely unchanged since 1942. 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. However, our work goes beyond this. We wish to pioneer new understanding into the regulation of NIS so that we can apply this to a number of different settings. For instance, via collaborators we will also apply our findings to models of NIS gene delivery and tumour spreading. We hope our work will inform the research of colleagues around the world who already exploit NIS function in multiple settings, adding new insight to these approaches. This ambitious programme of work will therefore use cutting edge approaches to solve the problem of systemically inducing NIS function.
