Identifying novel therapeutic strategies for endocrine cancers

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.