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.
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.
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.
Organisations
- University of Birmingham (Lead Research Organisation)
- University of Ferrara (Collaboration)
- EVOTEC (Collaboration)
- Ohio State University (Collaboration)
- Ludwig Maximilian University of Munich (LMU Munich) (Collaboration)
- UNIVERSITY OF DUNDEE (Collaboration)
- KING'S COLLEGE LONDON (Collaboration)
- Spanish National Research Council (Project Partner)
- Vrije Universiteit Brussel (Project Partner)
Publications
Dhillon-Smith RK
(2019)
Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception.
in The New England journal of medicine
Fletcher A
(2020)
Targeting Novel Sodium Iodide Symporter Interactors ADP-Ribosylation Factor 4 and Valosin-Containing Protein Enhances Radioiodine Uptake.
in Cancer research
Imruetaicharoenchoke W
(2017)
Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF.
in Endocrine-related cancer
Nazeer R
(2019)
Adenovirus E1B 55-Kilodalton Protein Targets SMARCAL1 for Degradation during Infection and Modulates Cellular DNA Replication.
in Journal of virology
Read ML
(2016)
The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer.
in Molecular carcinogenesis
Read ML
(2022)
Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter.
in Cell chemical biology
Read ML
(2018)
PTTG and PBF Functionally Interact with p53 and Predict Overall Survival in Head and Neck Cancer.
in Cancer research
Thompson RJ
(2019)
Dimerization of the Sodium/Iodide Symporter.
in Thyroid : official journal of the American Thyroid Association
Torlinska B
(2019)
Patients Treated for Hyperthyroidism Are at Increased Risk of Becoming Obese: Findings from a Large Prospective Secondary Care Cohort.
in Thyroid : official journal of the American Thyroid Association
Watkins RJ
(2016)
Pro-invasive Effect of Proto-oncogene PBF Is Modulated by an Interaction with Cortactin.
in The Journal of clinical endocrinology and metabolism
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 |