About the Project
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), therefore making the relationship between menin and chromatin remodelling via histone modification (epigenetics) 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.
Funding Notes
Funding for this project is available to basic scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.
For October 2017 entry, the application deadline is 6th January 2017 at 12 noon (midday).
Please visit our website for more information on how to apply.