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Neuroendocrine cells act as an interface between the nervous and endocrine systems, releasing hormones into the blood as a result of neuronal signals. Tumours arising in these cells are designated neuroendocrine tumours (NETs). NETs can be benign or malignant and occur in multiple organs including the pancreas, gastrointestinal tract and pituitary.

Patients with NETs may suffer significant morbidity due to hormone over-secretion e.g. increased insulin secretion resulting in low blood sugar and seizures, and malignant NETs usually present at an advanced, metastatic stage. The optimal treatment for NETs is surgery, however, this does not cure metastatic disease and conventional therapies are largely ineffective i.e. chemotherapy and radiotherapy (Thakker, et al. 2012), making NETs an important target for novel therapies.

Over 40% of sporadically occurring NETs are due to mutations of the gene MEN1, which leads to loss of activity of the encoded protein, menin. Additionally, patients with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by mutations of the MEN1 gene, develop multiple NETs. Menin is tumour suppressor protein with roles in transcriptional regulation, genome stability and cell division. Our group has previously characterised the growth of NETs and investigated novel therapeutic strategies, including replacement of the menin gene using an adenoviral vector, or monthly treatment with somatostatin analogues, in our established in vivo model (Harding, et al. 2009; Walls, et al. 2012; Walls, et al. 2016). With the emergence of the menin crystal structure, it has been shown that menin can bind multiple proteins including the histone methyltransferase MLL1 (Huang, et al. 2012). In addition, chromatin remodelling genes are frequently mutated in pancreatic NETs, and histone modifications have been identified in pituitary NETs (Karpathakis, et al. 2013), and we have shown JQ1 to have efficacy in reducing proliferation and increasing apoptosis of PNETs (Lines, et al 2017). The relationship between menin and chromatin remodelling via histone modification (epigenetics) is therefore a novel target area for NET therapies.

The objective of this DPhil project is therefore to build on the current work of the group targeting menin, to develop novel NET therapies. The student will test the ability of compounds that inhibit the activity of histone modifying proteins to reduce NET cell proliferation in vitro, and reduce NET growth in vivo, both alone and in combination with drugs currently used in the clinic. The mechanisms by which these compounds act, will also be investigated, focusing predominantly on the interaction of menin and epigenetic modifications, to gain greater insight into the proteins involved in NET development and growth.           

Training Opportunities

The project would be based at the Oxford Centre for Diabetes, Endocrinology and Metabolism. This DPhil would provide training in a wide range of basic molecular biology techniques including Western Blot, PCR and immunohistochemistry; cellular biology techniques including cell culture, cell transfections, proliferation assays, apoptosis assays, flow cytometry analysis and microscopy; as well as the use of in vivo mouse models. The successful applicant will be co-supervised by Dr Kate Lines, a postdoctoral research assistant within the group who is experienced in the above-mentioned techniques.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.

Publications

1

Harding B, Lemos MC, Reed AA, Walls GV, Jeyabalan J, Bowl MR, Tateossian H, Sullivan N, Hough T, Fraser WD, et al. 2009 Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Endocr Relat Cancer 16 1313-1327.

2

Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, Wan K, Merchant JL, Hua X & Lei M 2012 The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482 542-546.

3

Karpathakis A, Dibra H & Thirlwell C 2013 Neuroendocrine tumours: cracking the epigenetic code. Endocr Relat Cancer 20 R65-82.

4

Lines KE, Stevenson M, Filippakopoulos P, Muller S, Lockstone HE, Wright B, Grozinsky-Glasberg S, Grossman AB, Knapp S, Buck D, Bountra C & Thakker RV. 2017 Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumours. Oncogenesis 6(5):e332

5

Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F & Brandi ML 2012 Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97 2990-3011.

6

Walls GV, Lemos MC, Javid M, Bazan-Peregrino M, Jeyabalan J, Reed AA, Harding B, Tyler DJ, Stuckey DJ, Piret S, et al. 2012 MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas. Cancer Res 72 5060-5068.

7

Walls GV, Stevenson M, Soukup BS, Lines KE, Grossman AB, Schmid HA & Thakker RV 2016 Pasireotide Therapy of Multiple Endocrine Neoplasia Type 1-Associated Neuroendocrine Tumors in Female Mice Deleted for an Men1 Allele Improves Survival and Reduces Tumor Progression. Endocrinology 157 1789-1798.

Research Themes, Tools and Technologies

Supervisors

Key Dates for October 2018 Entry

Application deadline:  12 noon GMT on Monday 8 January 2018

Interviews for shortlisted candidates: Week commencing Monday 22 January 

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How to apply

To apply for a place on the DPhil in Medical Sciences you will need to submit an application using the online application form.

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