Molecular Mechanisms and Therapies for Parathyroid and Neuroendocrine Disorders

Lead Research Organisation: University of Oxford
Department Name: Unknown

Abstract

Abnormal hormone secretion from endocrine glands can disrupt the regulation of many body processes, thereby causing diseases in different organs. This is well illustrated by disorders of parathyroid hormone (PTH) which regulates body calcium, by controlling the balance between the amounts that are absorbed from the gut, deposited into bone and into cells, and excreted from the kidney. Over-secretion of PTH due to parathyroid tumours, which affect 3:1,000 of the adult population and 1% of postmenopausal women, is the major cause of a rise in plasma calcium and may be associated with kidney stones, renal failure, osteoporosis and ulcers. Moreover, parathyroid tumours can occur in association with other endocrine tumours that involve neuroendocrine cells of the pancreas and pituitary. These neuroendocrine tumours may also occur as isolated endocrinopathies that affect 5.5:1,000 adults. The pancreatic neuroendocrine tumours may be associated with ulcers, diarrhoea, and seizures due to a low plasma glucose; and the pituitary neuroendocrine tumours may be associated with infertility, impotence, high blood pressure and diabetes. Current treatments for these endocrine tumours are not always effective, and a better understanding of their causes, which are likely to have a genetic basis, will facilitate improvements in diagnosis and treatments. We have therefore been pursuing studies to identify these genes with the aims of elucidating the underlying mechanisms in these disorders of parathyroid and neuroendocrine tumours. In the course of these studies we have characterised the genetic abnormalities and mechanisms for 14 disorders of calcium homeostasis and bone metabolism, kidney stones and endocrine tumours. We have also translated these advances to: improve diagnosis and management; formulate guidelines; establish proof of principle for gene replacement therapy for endocrine tumours in a mouse model; and identify abnormalities in cellular signalling pathways. We now propose, in a continuation of this programme, to elucidate further the functions of the genes that we have recently identified, and to develop new avenues for drug design and gene therapy. This is likely to have further clinical impacts in the management of patients with parathyroid and neuroendocrine tumours, kidney stones, renal failure and osteoporosis. The results are published in high quality journals, presented at national and international conferences, and form the basis of contributions to book chapters and review articles. The applicant has also provided expert information to the media (e.g. New York Times), patient supports groups (AMEND), and he will continue to undertake this.

Technical Summary

Our research is focussed on investigating the molecular mechanisms underlying parathyroid and neuroendocrine disorders, with the aim of translating these advances into clinical practice by facilitating improvements in diagnosis and management, and of establishing in vitro and in vivo models for exploring new pharmacological and gene replacement therapies. Parathyroid tumours are common and major causes of abnormal calcium and bone metabolism, and may occur as an isolated endocrinopathy or in association with neuroendocrine tumours (NETs) of the pancreas and pituitary, as in multiple endocrine neoplasia type 1 (MEN1). During 2004-2009, we showed that: mutational analysis can solve diagnostic errors due to MEN1 phenocopies which occur in 5% of families; asymptomatic children with MEN1 mutations harbour non-functioning pancreatic NETs, thereby indicating a revision of the current international guidelines for screening; patients with germline MEN1 mutations may develop only parathyroid tumours and not NETs, implicating a role for genetic modifiers; pituitary NETs with loss of the MEN1 gene have abnormalities of proliferative (Wnt/beta-catenin) and apoptotic (Bcl2) pathways, down-regulation of tumour suppressor microRNAs (miR-15a-miR16-1) and upregulation of oncogenic microRNAs (miR130b); Men1 gene replacement therapy can decrease the proliferation rate of pituitary NETs in Men1+/- mice; inactivating mutations of the calcium-sensing receptor (CaSR), a G-protein coupled receptor (GPCR), which cause familial benign hypocalciuric hypercalcaemia type 1 (FBHH1) can be associated with parathyroid tumours in adults; an allosteric modulator of the CaSR can correct hypocalcaemia in a mouse model with an activating CaSR mutation that represents a model for autosomal dominant hypocalcaemic hypercalciuria type 1 (ADHH1); mutations in the G-protein, Galpha11, are associated with FBHH2 and ADHH2; and patients with FBHH3 have involvement of an as yet unidentified gene on chromosome 19q13. We now propose in a continuation of this programme to elucidate: 1) the genetic mechanisms and pathways underlying parathyroid and neuroendocrine tumourigenesis, by investigating the roles of the Galpha11, FBHH3, and MEN1 genes, and microRNAs; and 2) undertake pre-clinical studies using in vitro and in vivo models that would facilitate the implementation of new treatments e.g. targeted-peptides, gene therapy and microRNA therapy, for NETs and disorders of calcium homeostasis. Knowledge gained from these studies, will contribute to improved diagnostic and therapeutic strategies in these endocrine disorders. My group has made internationally leading contributions to this field which is ideally placed at the basic science and clinical interface, and fits with the MRC strategic priorities of: genetics and disease; and translation of research.

Publications

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Brandi ML (2016) Management of Hypoparathyroidism: Summary Statement and Guidelines. in The Journal of clinical endocrinology and metabolism

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Clarke BL (2016) Epidemiology and Diagnosis of Hypoparathyroidism. in The Journal of clinical endocrinology and metabolism

 
Description Clinical guidelines for neuroendocrine tumours
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact These guidelines will improve survival, quality of life and clinical practice. Published: Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, Corrie P, Davar J, Davies AH, Lewington V, Meyer T, Newell-Price J, Poston G, Reed N, Rockall A, Steward W, Thakker RV, Toubanakis C, Valle J, Verbeke C, Grossman AB (2012). Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut, 61: 6-32.
 
Description Clinical guidelines on multiple endocrine neoplasia type 1
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact These guideliines will have impact on improvements in clinical service. Published: Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Tonelli F, Brandi ML (2012). Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). Journal of Clinical Endocrinology & Metabolism, 97: 2990-3011.
 
Description Collaborative Grant
Amount £150,000 (GBP)
Organisation Novartis 
Sector Private
Country Global
Start 10/2012 
End 10/2014
 
Description Collabortive Grant
Amount £120,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2011 
End 10/2012
 
Description EU Marie Curie Initial Training Network - V Babinsky
Amount £160,000 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 10/2011 
End 09/2014
 
Description PhD Studentship - C Gorvin
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description PhD Studentship - K Gaynor
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2007 
End 09/2010
 
Description Rare Diseases Translational Research Collaboration
Amount £315,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 10/2013 
End 12/2016
 
Description Treat-OA
Amount £500,000 (GBP)
Funding ID 200800 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2008 
End 12/2012
 
Description Wellcome Trust Clinical Training Fellowship - A Rogers
Amount £200,000 (GBP)
Funding ID 099896/Z/12/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 09/2015
 
Description Wellcome Trust Clinical Training Fellowship - M Javid
Amount £200,000 (GBP)
Funding ID 087332/Z/08/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description Wellcome Trust Clinical Training Fellowship - S Howles
Amount £200,000 (GBP)
Funding ID 097099/Z/11/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Brown, S 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
Sector Public 
PI Contribution Undertaken molecular genetic studies and mouse phenotyping analysis together with details for publication.
Collaborator Contribution Brought together different expertise and resources to answer a biological question.
Impact 20457824
 
Description Cox, R 
Organisation Medical Research Council (MRC)
Department The Mary Lyon Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Undertaken molecular genetic studies and mouse phenotyping analysis together with details for publication.
Collaborator Contribution Brought together different expertise and resources to answer a biological question.
Impact Several papers, full details under publications.
 
Description Dr M P Whyte, USA 
Organisation Washington University in St Louis
Country United States 
Sector Academic/University 
PI Contribution Undertook molecular analysis and detailed scientific studies for the XLHPT project published in JCI 2005.
Impact 19809483 16167084
 
Description AMEND Patient Support Group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Approximately 200 patients and their relatives attended the talk which raised important and interesting questions with discussions thereafter. The venue was at a hotel in Rugby (UK) over a weekend.

Raised interest amongst patients for the need for medical research.
Year(s) Of Engagement Activity 2012
 
Description Association of Multiple Endocrine Neoplasia Disorders (AMEND) patient support group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Helping to produce newsletters, and a video / DVD for patients. Also helping to establish similar patient groups in Europe (meeting held in Italy 2010).

AMEND support group have reported a high level of interest in the video and are making copies to be distributed internationally.
Year(s) Of Engagement Activity 2010,2011
 
Description Placement for 6th form school pupil 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Encouraging school pupils to take up careers in medicine and science.

Student is plannign to apply to medical school.
Year(s) Of Engagement Activity 2011
 
Description Placement for undergraduate student 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Undergraduate student undertook a research project for one month and continued for the next year on a part time basis to complete this for final honors degree.

Degree obtained. Presentation of abstract at national British Endocrine Societies meeting.
Year(s) Of Engagement Activity 2009
 
Description Work placement for undergraduate. 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact One student worked in the lab for one month.

One abstract and one peer reviewed publication achieved.
Year(s) Of Engagement Activity 2010