Meet the Endocrinologist: Professor Thakker, endocrine neoplasia expert

Professor Rajesh Thakker, Fellow of the Royal Society and May Professor of Medicine at the University of Oxford, specializes in Multiple Endocrine Neoplasia 1 (MEN1) and neuroendocrine tumours (NETs). He tells us more about his career inspirations, advances, challenges and opportunities within the field, both in clinical research and practice, and how his role as Endocrine Neoplasia Syndromes Network Convenor supports his work. 

What inspired you into endocrinology, and why did you then focus on neuroendocrine tumour research?

This began with a patient, as is often the case for physician-scientists. Whilst studying Natural Sciences at Cambridge, I developed an early interest in endocrinology. Later, as a registrar at The Middlesex Hospital in London, I was admitting a young woman, from A&E, with severe hematemesis due to a peptic ulcer. She also had a history of renal stones due to primary hyperparathyroidism; and further investigation showed she had a prolactinoma. All this indicated that she had multiple endocrine neoplasia type 1 (MEN1), a genetic disorder inherited as an autosomal dominant trait.

At the time, the genetic defect and the underlying molecular and cellular mechanisms causing MEN1 were unknown. Fortunately, I was then working with Jeffrey O’Riordan, who had expertise in endocrinology and calcium homeostasis, and who encouraged me to pursue research. Moreover, looking after patients with endocrine disorders led me to realise two things. First, that there were still many gaps in our knowledge of the underlying mechanisms of endocrine conditions; and second, that these mechanisms could be elucidated through the recent advances in molecular biology.

This was exemplified by an inspiring lecture, by Jack Martin, on the identification of parathyroid hormone-related peptide (PTHrP), as the humoral factor causing the hypercalcemia of malignancy. During the lecture, he illustrated the usefulness of the molecular approach to understanding fundamental disease processes. Deeply excited by this discovery and its scientific approach, I put my efforts into obtaining a Medical Research Council (MRC) clinical training fellowship, to further the understanding of the biological mechanisms involved in endocrine disorders.  Since then, as a physician-scientist, I have been engaged in the investigation of the molecular genetics of endocrine diseases – a constant source of challenge and excitement in uncovering the underlying biological mechanisms that cause human disease.

Can you tell us a little about your current research and clinical work? 

My current research focuses on two main areas. The first is to identify genes whose mutations are involved in causing endocrine tumours and diseases – and area where the advances of next generation sequencing have tremendously helped, and where there is enormous potential to make new discoveries and translate them for patient benefit. The second area explores the mechanisms of G-protein coupled receptor (GPCR) signaling – we have recently identified a non-canonical pathway in which signaling by the calcium-sensing receptor (a GPCR) involves endosomes. Targeting this non-canonical endosomal pathway may elucidate novel signaling targets that could be altered by pharmacological compounds.

Over the last decade or so, what do you think have been the most significant advances in neuroendocrine tumour clinical practice, and/or research?

The implementation of genetic testing has been very useful – it had a major impact in the diagnosis and management of patients with endocrine tumour syndromes, such as multiple endocrine neoplasia. Screening for these tumours, including neuroendocrine tumours, results in their earlier detection and treatment. On the research front, the introduction of many new treatments, e.g. tyrosine kinase inhibitors and mTOR inhibitors, as well as some emerging therapies such as epigenetic modifiers and gene therapy, which are in the pre-clinical stages, have been very significant.

What do you think will be the next big or important breakthrough for treatment or diagnosis of neoplasia syndromes?

The next big breakthrough for diagnosis is likely to be the advent of enhanced imaging modalities that will detect the tumours at an early stage, together with molecular biomarkers that will help their detection and monitoring. When it comes to treatments, the next big step is likely to involve emerging compounds such as monoclonal antibodies, agents targeting oncogenic pathways, radionuclide therapy and epigenetic modifiers.

What do you think are the biggest challenges faced by your clinical specialty?

The biggest challenges faced by our clinical specialty, and indeed all clinical specialties, are the difficulties in the training programmes of our younger doctors. Morale amongst the young doctors is low, and they feel undervalued. This is totally counterproductive, as we attract the brightest and most talented students into medicine, and yet the current organizational infrastructure and systems seem to thwart their talents and abilities rather than allowing them to thrive and expand and achieve their aspirations.  These difficulties are due to multiple factors that include:

  • lack of flexibility in training pathways;
  • the rotas, which are often not provided well in advance and are rigid such that forward planning for leave is precluded, and have gaps that result in increased workload for the doctors and a strain in the provision of service;
  • the absence of a clinical firm with senior doctors (consultants) that provide role models, inspiration and encouragement for the younger generation to aim high, and to support them in their careers.

All of this has resulted in diminished attractiveness for the role of the “medical registrar”, with a decrease in recruitment of top caliber doctors. We need to act fast to rectify the current situation if we are going to maintain the high excellence of our medical practice and its vital underpinning by scientific advances. To achieve this, all the learned societies and NHS need to work with the Royal Colleges to deliver on the recommendations made by the report “The medical registrar: Empowering the unsung heroes of patient care” (The Royal College of Physicians, March 2013), and thereby improve the situation for our younger doctors.

Are there any controversies in your practice area? How do you think they will be resolved?

There are many controversies in the diagnosis and management of NETs, which largely stem from a lack of adequate clinical trials that would provide evidence of their efficacy – thus, we are reliant on expert opinions that aren’t always in agreement. In rare diseases such as NETs, it would be important for experts from multiple centres to collaborate, designing studies to evaluate the methods used for diagnosis and treatments, so that the most effective tests and treatments can be implemented in a standardised manner for our patients.

What do you enjoy about being an Endocrine Neoplasia Syndromes Network convenor, and how do you think it may benefit others?

It is a privilege to work with enthusiastic colleagues at different career stages, and to have a free exchange of ideas between scientists, clinician-scientists and clinicians, all of whom have a “can-do” approach.  As a convenor, I have learned a lot from my colleagues and patients – the free debate that we have helps to advance the field and provide insights into the biology of the disorders, and to explore ways of benefiting our patients.

Do you have any words of wisdom for the younger generations of endocrinologists?

Endocrinology is a fascinating discipline – it will satisfy those who are intellectually curious, yet are equally keen to apply their knowledge to a practical setting.  Moreover, endocrinology embraces a diverse spectrum of biological and metabolic processes, whose dysregulation affects virtually every human disorder.  Furthermore, in the UK we have major international leaders in endocrinology, and there are ample and extraordinary opportunities for young endocrinologists to get top training in clinical endocrinology and basic science. Finally, we have outstanding funding organisations such as the Medical Research Council and the Wellcome Trust, which have an excellent track record in funding research in endocrinology.

Young endocrinologists can have a wonderful future in this discipline. My advice to aspiring endocrinologists would be to not ask what endocrinology can do for you, but to instead ask what you can do for endocrinology – you will then be assured of an exciting and satisfying career.


The Endocrine Networks are platforms for knowledge exchange and collaboration amongst basic and clinical researchers, clinical endocrinologists and endocrine nurses. The networks enable members to discuss and find solutions to challenges within their specialist field.

To join an Endocrine Network login to the ‘My profile’ section of the ‘Members’ Area and select Endocrine Networks.

Meet the Endocrinologist: Dr Carel le Roux, Consultant in Metabolic Medicine and Obesity Update speaker

Meet Dr le Roux, Consultant in Metabolic Medicine at Imperial College London and Chair of Experimental Pathology at University College Dublin. During his career, he successfully established an independent research group and has been an important influencer in the field of metabolic medicine. His research focuses on diabetes and obesity, specifically the increased morbidity and mortality associated with these conditions.

Dr le Roux will be speaking at Obesity Update 2018, in the debate ‘Will metabolic surgery replace pharmacotherapy for the treatment of type 2 diabetes?’ Ahead of the event, we interviewed him to find out more about his career path, research interests and his position in the upcoming debate.  

 Q: Tell us more about your background and career highlights so far?

I am a metabolic medicine physician with an interest in obesity; specifically in how bariatric surgery and pharmacotherapy can improve patient outcomes.  I graduated from the University of Pretoria and completed my specialist training in Metabolic Medicine at St Bartholomew’s Hospital and Imperial College. I was awarded a Wellcome Clinical Research Fellowship and completed my PhD at Imperial College. I then received an NIHR Clinician Scientist Award, which enabled me to set up the Imperial Weight Centre, and was then offered a Chair at the Diabetes Complications Research Centre at University College Dublin. The proudest moment of my career was receiving the President of Ireland Young Research Award at Áras an Uachtaráin.

Q: What are you currently working on?

My research investigates using a combined approach of bariatric surgery with pharmacotherapy to reverse the complications of diabetes. We are aiming to treat people with diabetic complications, e.g. diabetic kidney, renal, neural or cardiovascular disease, with both surgery and medication to put these symptoms into remission and stop the development of the disease.

Q: What most excites you about your work and the contribution you can make?

I am most excited about the opportunity to hear what obese patients report about their disease, and applying this knowledge together with basic and clinical science to pursue these symptoms and understand the mechanisms of obesity. I am also excited about the progress we have made in the field; for example, the discovery that obesity is a subcortical brain disease opens up new treatment options, while also reducing the discrimination that patients suffer.

Q: The theme of the 2018 Obesity Update debate is whether surgery is more effective than pharmacotherapy in the treatment of type 2 diabetes. Can you tell us why there is a difference of opinion on this?

Until recently, bariatric surgery – that is gastric by-pass or sleeve surgery – was not considered to be a viable treatment for patients with type 2 diabetes. However, a systematic review of 11 randomised controlled trials, published in 2013, showed that those who undergo surgery do better and outperform patients on pharmacotherapy for weight loss, glycaemic and blood pressure control. This, of course, has great implications for type 2 diabetes patients.

Given the aforementioned trials and their results the question becomes: should every type 2 diabetes patient be offered surgery as a treatment? However, the issue here is not really whether or not we should use surgery – but if and when bariatric surgery is the best strategy to follow.

Q: You will argue that surgery cannot replace pharmacotherapy but, if surgery is so successful, why not?

The main issue is that not all patients with diabetes are the same – the risks of morbidity or diabetic complications are extremely varied and thus, their treatment options should accommodate these differences and find a balance between the risks and gains of bariatric surgery vs. pharmacotherapy.

Although the risks associated with surgery are very low, they still aren’t as low as those associated with medication. Considering this, patients at high risk of diabetic complications for whom best medical treatment is not sufficient may hugely benefit from surgery. On the other hand, for those patients who respond positively to pharmacotherapy there is little value in offering surgery as well.

Additionally, we must not forget that pharmacotherapy is constantly improving. Due to such advances, if we had a randomised controlled trial today that compared outcomes between surgery and medical care, it would be very difficult to imagine that surgery would have any additional benefits beyond best medical care when it comes to mortality. We’d love to say that if you have an operation you’re going to live longer but we simply don’t have that evidence. However, we do have evidence to say that using drugs, such as a sodium-glucose co-transport inhibitor or a GLP-1 analogue, will help diabetes patients to live longer.

Q: In your opinion, when would bariatric surgery be appropriate?

We should offer surgery when it adds value to the patients – helping them to lose weight, and achieve better glycaemic and blood pressure control – and to facilitate the work of diabetologists that treat these patients. It’s not about surgery against medicine, it’s about how surgery can make medicine better. This is precisely what’s done in cancer therapy – we use surgery to control the disease, then chemo or radiotherapy to keep it in remission. We don’t expect surgery to be sufficient on its own – after surgery we still follow the patient and make sure to control all the other consequences of the surgery.

In summary, the model should shift to actually using surgery as an add-on therapy to pharmacotherapy. This way, the benefit of using surgery is that patients need much lower doses of medication. It may allow someone who needs insulin to control type 2 diabetes to move on to requiring only metformin or other oral medications. That would be a massive improvement for the patient’s quality of life. Taking it a step further, a patient with fully controlled diabetes on oral medication could use surgery to put diabetes into remission, and then use a lower dose of metformin to keep the diabetes in remission.

Q: How do you think this debate be resolved?

I think we will all agree that more surgery should be offered to patients; and that we need to use this combined treatment model more frequently in patients with diabetes, especially for those that would benefit most. However, it is how this cohort of patients will be defined that will provoke further debate.

Q: What do you enjoy doing in your spare time?

I have recently started sailing Flying Fifteens and am currently training to qualify for the World Championships in 2019.

Q: Who do you admire most and why?

Rodin – as a sculpture artist he was able to communicate very complex concepts using the human body, but he did so in a simplistic way that influenced how people thought, thus moving civilization forward.

Obesity Update 2018, an event sponsored by the Society for Endocrinology and the Association for the Study of Obesity, will be held in London, 1 February 2018. Register now to attend.

Meet the Endocrinologist: V. Craig Jordan, Endocrine-Related Cancer author, reviewer and reader

Meet Professor V. Craig Jordan, Professor of Breast Medical Oncology and Molecular and Cellular Oncology at MD Anderson Cancer Center, University of Texas, leading light in cancer research, and father of the ground-breaking breast cancer drug tamoxifen.

Ever since he favoured studying pharmacology at university over drumming in a rock band, Jordan focused his efforts into developing a thriving career in endocrine breast cancer research. His current work focuses on how oestrogen-induced apoptosis can help prevent breast cancer recurrence after tamoxifen treatment. Jordan’s numerous scientific merits have led to him receiving many awards, including an OBE for services to international breast cancer research and being appointed Honorary Fellow of the Royal Society of Medicine (UK), Fellow of the Academy of Medical Sciences (UK), and Elected Member of the National Academy of Sciences (US).

Following Jordan’s guest review published in Endocrine-Related Cancer, we spoke to him about his career highlights and asked for his advice to early career researchers.

Q: What has been your proudest professional experience so far?

To date, my proudest experience has been to successfully reinvent ICI 46,474, a failed contraceptive, as tamoxifen, one of the most valuable breast cancer medicines that we have today. Back in the 1970s no one was interested in medicines that did not kill cancer, and early clinical experience with tamoxifen in metastatic breast cancer demonstrated only palliative activity. When our work started, it was chemotherapy that was on the spotlight – it was what was going to cure cancer.

My career development was accelerated by guidance from my mentors Paul Carbone, Bill McGuire, Elwood Jensen, and Harold Rusch; and the success of tamoxifen in the 1980s brought me to the University of Wisconsin, where my Tamoxifen Team discovered Selective Estrogen Receptor Modulators (SERMs). Tamoxifen was the pioneering SERM – there are now five different FDA approved SERMs for multiple indications in women’s health, ranging from treatment and prevention of breast cancer, osteoporosis, alleviation of menopausal symptoms and dyspareunia.

I have personally been delighted at the success of my Tamoxifen Team members, both in academia and the pharmaceutical industry. The development of SERMs was always a team effort, and my election to the National Academy of Science and National Academy of Medicine (and the equivalent in the United Kingdom, Fellow of the Academy of Medical Sciences and Honorary Fellow of the Royal Society of Medicine) is an honour I share with my Tamoxifen Teams.  The Tamoxifen Team is on the Wall of Honour at the Royal Society of Medicine in London.

Q: What in your working life are you most passionate about?

First of all, I am and have always been passionate about giving opportunities to the young trainees in my Tamoxifen Teams. “We are in it for life” is our team motto – over the last 40 years team members have had my support, and will continue to have it for the rest of their lives. Secondly, my academic passion is focussing on research that can potentially aid the survival of women with breast cancer. And finally, I have had a 40-year long love affair with the triphenylethylene molecule, the oestrogenic basis of the anti-oestrogen tamoxifen. I continue to have a focused interest on the relationship of SERMs with the oestrogen receptor.

Q: What most excites you about your work and the contribution you can make?

Our work on SERMs and acquired resistance to long-term anti-hormone therapy in breast cancer produced some important surprises of clinical significance. Our study of acquired resistance to tamoxifen in the laboratory resulted in our finding that, following long-term anti-oestrogen treatment (5 years), low concentrations of oestrogen kill breast cancer cells. This has clinical significance in physiology and the treatment of breast cancer, a topic which I recently reviewed in Endocrine-Related Cancer (Jordan, VC, 2015, Endocrine Related Cancer. 22:R1 – R31). Moving to the MD Anderson Cancer Center, University of Texas, provides an opportunity to extend the lives of women with new treatment strategies following the diagnosis of breast cancer. These are exciting times as it is clear that around the world our knowledge of breast cancer is accelerating. We must know our enemy in order to destroy it!

Q: What is the best feedback or advice you have ever received?

Early in my career there were two memorable moments where individuals changed my perspective.

I was not a good student during grammar school.  I had one interview at Leeds University, Department of Pharmacology, and was lucky to get into university in 1965. My goal was to use organic chemistry to develop drugs to treat cancer. However, a year into my degree I was uncertain I was doing the right courses to get into cancer research. I was then interviewed by Dr Mogey, who was to decide on my change of course. My meeting with Dr Mogey did not go well – he chose to give me honest feedback. He looked at my poor performance to date, stared at me over his half-moon glasses, and said “I don’t think you are good enough to transfer”. In response, I stood up and announced that I would become top of the third year organic chemistry course I was then doing, get a first class pass in biochemistry, and pass my physics course despite the fact I had never taken physics before. I stormed off and narrowly missed smashing his glass door as I slammed it. At that point I learned that either you chose to fight, or you fold. I chose to fight, but not to transfer courses because of my love of chemistry.

Years later I discovered two things about Dr Mogey. Firstly, he recommended me for a prestigious Ackroyd scholarship, which I won for my exam performance in my first year at Leeds. Secondly, he wrote a letter of recommendation for me to become a faculty member in his pharmacology department. Thanks to Dr Mogey’s feedback, I learned the qualities that it took to be an honest and good faculty member, and how to fight to succeed in a chosen path.

Similarly, when I was a visiting scientist at the Worcester Foundation in 1974, a Dr Eliahu Caspi called me into his office for an interview to decide, based on documented performance, whether I was to be offered a job there and not return to England. At the interview, he picked up my CV, glowered at me over his desk and stated “you don’t have a CV, because you haven’t published anything”. This hammer blow was another Mogey moment. I replied that I couldn’t publish because I had still not discovered anything. His advice then was to tell the story so far; to connect my publications together so that I could have a theme – and this became my working model.

Q: Based on your experience, what qualities or skills do you feel young scientists need to be successful?

I believe there are two essential skills that every young person must master. Firstly, without the ability to stand up and give a presentation you cannot communicate with your colleagues. Secondly, it is fundamental that you become encyclopaedic about your topic of research. The postdoctoral fellows of my current Tamoxifen Team at the MD Anderson Cancer Center are required to present historical papers from past Tamoxifen Teams – not only to hone their presentation skills, but also to learn about the development of models that we have created in the past and still use for our experiments today. After six months of presentations, I consider these trainees to be fully prepared to go into scientific meetings with enough confidence and a sound background of relevant knowledge.

Q: What advice would you give early-career researchers when thinking about publishing their work?

We return to Dr Caspi, who we met earlier in this interview and who advised me to publish. I echo his advice – if you do not publish the results you have found and tell the story so far, you have never done the work. If it’s not in print, it never happened; and you cannot claim primacy of an idea.

Every ambitious young person first wants to publish in Nature or the Proceedings of the National Academy of Sciences, which I don’t think is a good plan to start with – it helps the mentor’s reputation, not the young researcher’s. When I returned to the University of Leeds from the Worcester Foundation in 1974, I decided to publish my work in the Journal of Endocrinology, the European Journal of Cancer and, since I was a pharmacologist, the British Journal of Pharmacology. Between 1974 and 1980 I published 11 referred articles in the Journal of Endocrinology. I wanted to create impact for my work on the new anti-cancer drug tamoxifen. In 1975, I attempted to publish three papers on tamoxifen in a single issue of the Journal of Endocrinology, and almost succeeded! So my second piece of advice is to attract attention, and to publish in journals from professional societies. I published my highest cited (445) scientific paper on tamoxifen in the Journal of Endocrinology; a paper that turned out to become the blueprint for all future SERMs over the next decade.

Q: What do you enjoy doing in your spare time?

For me this has always been age dependant. As a young man at Leeds University, between 1966 and 1979, I was an Army Reserve Officer in the Intelligence Corps, and remained with the Special Air Service as a Regular Army Reserve Officer until the age of 55. During the past two decades I have enjoyed the beautiful mountains of the Austrian Tyrol and international travel. During the last decade I have taken much pleasure in my library of 6,000 hardback books and, over the years, in the exchanged correspondence with several of the authors who are soldiers, scientists, TV presenters and one spy.

Q: Who do you admire most and why?

I admire individuals who, against all odds, can achieve success in an activity that advances society.

Dr Margaret Foti is the CEO of the American Association for Cancer Research (AACR), the oldest cancer research organization in the world. She initially joined the AACR as an editorial assistant for their single journal Cancer Research and became the youngest managing editor of a major scientific journal in the country. Under her leadership, the AACR membership has grown from 3,000 to 37,000 with representatives from 108 countries. The journal portfolio has grown from 1 to 8 major scientific journals. She worked for a PhD along the way and was honoured with an MD. Marge is the modern AACR.

Dr Angela H. Brodie died on June 7, 2017. Angela told her students to do research that serves to help mankind. She trained as an endocrinologist and, together with her husband Harry, discovered the first selective aromatase inhibitor. At that time no companies were interested in developing an aromatase inhibitor to treat breast cancer, so Angela did it herself. The medicine was synthesised at the University of Maryland, shipped to England and tested showing positive results. She succeeded when others would not have given battle. Her determination resulted in the development of three FDA aromatase inhibitors and hundreds of thousands of lives saved. Angela had a calm, shy personality, but a will of steel.

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Conference delegate SOS – help get our research proposals off the ground!

SfE BES is all about bringing endocrine professionals together to share knowledge and spark future collaborations. This year, for the first time, delegates are invited to hear specific research proposals and contribute their insights, data or resources to really help get these fledgling projects off the ground.

Here, Dr Kate Lines, from the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, talks about her proposal to be presented at an Endocrine Network Research Incubator Meeting to further understanding of pancreatic neuroendocrine tumours. To complete her project, she needs SfE BES 2017 delegates to provide more patient samples!

My research mainly focuses on learning more about how pancreatic islet cell tumours (pancreatic neuroendocrine tumours) grow, and using this information to develop new therapies. One specific area that has begun to interest me recently is inflammation. Inflammation is a process in which the body sends cells of the immune system (or white blood cells) to specific areas to defend against foreign substances. It has now been shown that many tumours can hijack this system by releasing chemicals to lure in white blood cells. Once the white blood cells reach the tumour they are encouraged to secrete small proteins (cytokines), which help make the perfect environment for the tumour to grow. The perfect growth environment is different for different tumours, therefore the specific white blood cells and cytokines needed by each tumour is also different. Currently, not much is known about which white blood cells and cytokines are most important for supporting pancreatic neuroendocrine tumours.

I submitted a proposal for the Endocrine Neoplasia Syndromes Network Research Incubator Meeting at SfE BES 2017 that suggests examining the area around dissected tissue from pancreatic neuroendocrine tumours for these specific cells and cytokines. Once we have this information we can use it to either help diagnose the tumours (as the cytokines can be detected in the blood), or target them with specific drugs to try to make the environment less ideal for the tumour to grow. However, the trouble with pancreatic endocrine tumours is that although they can be deadly, they are also rare. This is the main stumbling block for the proposed study, as our hospital alone doesn’t have enough samples for us to be confident that the specific cells and cytokines we see are representative of those occurring in all patients.

The Endocrine Neoplasia Syndromes Network Research Incubator Meeting provides a rare opportunity for us to try to access these samples from different hospitals in different locations, which ultimately could provide a set of samples that is truly representative of all the pancreatic neuroendocrine patients in the UK. Not only could the members help by providing samples for this study, but as our work continues they could also provide further samples, such as blood, for future work stemming from this proposal. I therefore hope that the other members of the network will be as interested in this area as I am and would like to provide us with lots of patient samples to investigate. In addition, as an early career researcher it is rare to get the chance to present new ideas to my peers. I am therefore looking forward to what I hope will be an exciting and stimulating discussion on a new area of research for me.

The Endocrine Network Research Incubator Meetings will take place on Tuesday 7 and Wednesday 8 November, 07:45–08:30, come along to the Endocrine Network Meeting most relevant to your research interests and read the full scientific programme for SfE BES 2017 for more details.

To join an Endocrine Network login to the ‘My profile’ section of the ‘Members’ Area and select Endocrine Networks.