RE-ENGINEERING RADIOIODINE THERAPY FOR THE 21ST CENTURY

The newest data available show us that nearly 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 (radioiodine 131I). For these patients, life expectancy is significantly reduced. Importantly, around 38,000 people die from thyroid cancer per annum.
Radioiodine is a safe and effective treatment which has been in clinical use for 73 years. However, its utilisation has remained largely unchanged since 1942. It is our assertion that new breakthroughs and technologies could transform radioiodine 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 its activity are not completely understood. Our project aims to change this through an ambitious series of high level experiments, calling on our existing data, and via the generation of new insight. We will use cutting edge cell and animal experiments to isolate the utterly best way of improving the function of NIS, and hence the efficiency of thyroid cancer treatment.
Through our existing long term commitment to this project, we have already found a way of increasing 131I uptake into cells by at least 70%. Now, we need to discover whether we have reached the maximum possible improvement in the therapy, or whether new technologies can transform this effect and make the treatment even more effective and applicable. To do this we will establish new models which bridge the gap between assays based on 'classical' cell culture (mainly isolated cells in monolayer), and biological validation in whole animals such as rodents. We will engage with drug companies and world leading scientists to carry out an ambitious joined up and intensive period of research with the overall goal of finally making 131I uptake a viable and effective treatment for all patients with thyroid cancer.

We will utilise a combination of straightforward technical approaches, new in vivo models, and challenging experimental systems. We will refine our existing pathway of increased radioiodine uptake via targeted inhibition of Src phosphorylation of PBF to determine whether we can we improve upon the 70-100% enhanced radioiodine uptake efficacy we have achieved via combination treatment. Thus, we will screen additional TKIs and N-myristoyltransferase inhibitors (NMTis) at increased resolution via real time and time lapse microscopy studies, and via cell surface biotinylation assays. In parallel, we will explore in high throughput screening via our commercial partner Evotec whether any of 6,000 annotated compounds modulating central cellular signalling pathways alter NIS function, and, via HTS PE OPERA screening, PM localisation. Subsequently, we will perform in vivo screening in double transgenic zebrafish embryos. Screening of the corresponding stable transgenic zebrafish lines will elucidate whether drug treatments identified in vitro alter NIS function in vivo. We will then progress to mESC differentiated into thyroid follicular cells organised into follicles via doxycycline treatment to induce expression of NKX2.1 and PAX8. Functional in vitro follicles will be subject to the optimal drug treatments identified thus far. ESC-derived thyroid follicles will be grafted into hypothyroid mice and drug treatments altering follicular uptake of radioiodine will be appraised in grafted ectopic thyroid glands. Finally, we will perform real-time orthotopic tumour modelling in mice utilising transformed thyroid cell lines transduced with GFP-LUC for in vivo imaging. This will progress to 'high-risk, high payoff' experiments with human primary thyroid cultures from patients with thyroid cancer injected orthotopically into mice treated with the identified drug combinations and subject to ablative radioiodine treatment.

Worldwide, ~300,000 new cases of differentiated thyroid cancer (DTC) are reported per year. DTC now represents the most rapidly increasing cancer in the US and in the UK. In general terms, outcome is good (10-year survival >90%). However, patients whose disease is not responsive to radioiodine (131I) treatment have a life expectancy of 3-5 years and represent a group for whom there is a clear unmet medical need. Around a quarter of thyroid tumours do not uptake sufficient radioiodine for effective therapy, contributing to >38,000 worldwide deaths from thyroid cancer per annum.
To address this, we propose to perform innovative high-level basic and pre-clinical science to achieve our aim of re-engineering how we use radioiodine therapy for patients with thyroid cancer, including those for whom no other current treatment options exist. The impact will be potentially transformative. If we can extend and refine these types of approach, a longer term spin-out from our efforts may lie in radioiodine becoming a viable strategy in triple negative breast cancer, as well as prostate and other cancers currently being evaluated as engineered targets for radioiodine ablation. Thus the broader impact of our work upon human health has the potential to be of the utmost utility. We will aim to have significant impact at the following levels:

ACADEMICS - Our findings will directly impact upon the numerous scientists and clinicians currently engaged in research into NIS efficacy; the groups who are actively examining the potential of using radioiodine treatment in cancers other than the thyroid; and those academics more widely engaged in thyroid cancer research and patient treatment. Indeed, one of the main impacts of our work is the establishment and use of novel physiologically relevant models which will yield improved pre-clinical screening of NIS action

CLINICIANS - If successful, our experiments will, we hope, impact upon NHS policy makers, providing compelling data that short-term treatment (24 hours) with established and well tolerated drugs targeting NIS post translational modifications will result in an increased efficacy of radioiodine treatment for patients with thyroid cancer

PATIENTS - Our research will impact upon patients with thyroid cancer at two levels. First, and most generally, we anticipate that being able to enhance radioiodine treatment for all patients will reduce the incidence of recurrent and metastatic thyroid cancer. Second, our findings will be direct benefit to patients with radioresistant thyroid cancer, for whom no current modalities exist.

INDUSTRY - We are partnering with Evotec and the Dundee Drug Discovery Unit. This will facilitate access to technologies and screening platforms not currently available in our academic setting. The impact upon industry here will be via direct academic engagement into research which seeks to utilise and appraise new and existing drugs in novel therapeutic settings.

THE PUBLIC - Our findings will impact upon the public and patient groups, as we continue to actively contribute to patient/public engagement activities.

Through this project, and the implementation of its findings, we aim to fundamentally change the way patients with thyroid cancer are treated. Current treatments manage aggressive thyroid cancer as a chronic disease, and ultimately fail. Our approach is cytotoxic, rather than cytostatic, in that we will seek to bring about significantly enhanced tumour ablation. This has the potential to revolutionise patient treatment and outcome. Exposure to epigenetic drugs, TKIs and other modifiers will be transient around the time of radioiodine treatment, rather than long-term. The unpleasant side effects associated with, for example, long-term TKI treatment would therefore be negated. EFFICIENT EARLY ABLATION, RATHER THAN LATE-STAGE DISEASE MANAGEMENT, WOULD TRANSFORM THYROID CANCER TREATMENT AND PATIENT OUTCOME.