RE-ENGINEERING RADIOIODINE THERAPY FOR THE 21ST CENTURY

Lead Research Organisation: University of Birmingham
Department Name: Clinical and Experimental Medicine

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
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Dhillon-Smith RK (2019) Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. in The New England journal of medicine

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Imruetaicharoenchoke W (2017) Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF. in Endocrine-related cancer

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Thompson RJ (2019) Dimerization of the Sodium/Iodide Symporter. in Thyroid : official journal of the American Thyroid Association

 
Description Chair of the Wellcome Trust Basic Science Interview Committee
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Membership of NIHR Panel on Thyoid Cancer
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact We feed into multiple agenda-setting fora for the treatment of patients with thy cancer
 
Description FNAseq: Nanopore sequencing of FNA samples in thyroid cancer
Amount £20,000 (GBP)
Organisation British Thyroid Foundation (BTF) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2019 
End 05/2021
 
Description New clotrimazole analogues in thyroid cancer
Amount £99,986 (GBP)
Funding ID TBA 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2021 
End 11/2021
 
Title CRISPR mouse 
Description A mouse model of global PBF knockout 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2017 
Provided To Others? No  
Impact In progress; we will share this mouse if requested 
 
Title New method of HTS via YFP 
Description We adapted and scaled a new way of high throughput screening for cellular uptake 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? Yes  
Impact Too early 
 
Description Collabroation with Ferrara, Italy 
Organisation University of Ferrara
Country Italy 
Sector Academic/University 
PI Contribution We are hosting for 6 months a PhD student from a collaborator in Ferrara
Collaborator Contribution They are paying the PhD student's stipend
Impact Too early
Start Year 2020
 
Description Commercial partnership with drug screening company Evotec 
Organisation Evotec
Country Germany 
Sector Private 
PI Contribution We have instigated, driven and achieved funding for this.
Collaborator Contribution Providing drug screening input
Impact Outcomes pending
Start Year 2016
 
Description Dundee Drug Discovery Unit 
Organisation University of Dundee
Country United Kingdom 
Sector Academic/University 
PI Contribution Testing a new class of drugs
Collaborator Contribution Providing some new and exciting drugs
Impact Data for collaborative publication
Start Year 2015
 
Description Exogenous NIS function in Germany 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department University Clinic of Munich
Country Germany 
Sector Academic/University 
PI Contribution My PhD student spent 3 months at LMU learning new techniques
Collaborator Contribution My research partner hosted and trained my PhD student for 3 months
Impact Abstracts to come
Start Year 2019
 
Description Partnership with Kings College London 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We are providing drugs and expertise, and members of my group are regularly visiting the KCL labs
Collaborator Contribution KCL are collaborating and helping us perform SPECT/CT imaging in mice
Impact A successful grant application to DOD
Start Year 2019
 
Description Partnership with Ohio State University 
Organisation Ohio State University
Country United States 
Sector Academic/University 
PI Contribution Setting up of a collaborative bid for grant funding to be submitted in 3 weeks
Collaborator Contribution Setting up of a collaborative bid for grant funding to be submitted in 3 weeks
Impact A joint grant proposal to the DoD
Start Year 2020
 
Description Key Speaker, Wellcome Trust PhD Student Annual Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Key Guest Speaker to all UK Wellcome PhD students; advise on successful PhD progress
Year(s) Of Engagement Activity 2017
 
Description King Edwards School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Careers talk and advice to 6th form students on medical research
Year(s) Of Engagement Activity 2017
 
Description Presentation to Patient group/ Charity 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Keynote talk to charity, supporters and patients
Year(s) Of Engagement Activity 2019
 
Description Presentation to Wellcome Trust PhD Students 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Presentation and career workshop for 4th year Wellcome PGRs
Year(s) Of Engagement Activity 2016