Developing stem cell based models of MEN1-associated pancreatic neuroendocrine tumours (PanNETs) – a tool for drug discovery

Dr Paul Newey (Dundee)

Amongst the commonly occurring tumours in Multiple Endocrine Neoplasia type 1 (MEN1), pancreatic neuroendocrine tumours (PanNETs) present the greatest clinical challenge, not least because they are the leading cause of premature death in affected individuals. PanNETs frequently occur at an early age (i.e. <20 years) highlighting the need for tumour screening commencing in childhood. Currently, medical therapies targeting PanNETs are lacking and surgery remains the mainstay of treatment. However, PanNETs are frequently multiple and often recur after surgery. This, together with the inability to predict the clinical behaviour of such tumours, ensures that PanNETs cause considerable anxiety for affected individuals and their families. Thus, there is a clinical need to develop improved therapies aimed at preventing and/or treating such tumours. To date such progress is hampered by a lack of relevant cellular disease models in which to study MEN1 gene function and to evaluate new treatments.

To address this challenge, the aim of this study is to exploit very recent scientific advances to establish novel cell-based models of MEN1-associated PanNETs. To achieve this, specialised cells, known as induced pluripotent stem cells (iPSCs), will undergo a carefully orchestrated process known as ‘differentiation’ to generate human pancreatic endocrine cells in the laboratory. Once established, such cells will be used to investigate how damage to the MEN1 gene results in tumour formation, by evaluating the response of such cells to a potent MEN1 inhibitor. In addition, MEN1 mutations similar to those observed in MEN1 patients will be introduced into the cells and their effects on pancreatic endocrine cell behaviour assessed. Together, these approaches aim to replicate the environment found in pancreatic endocrine cells in individuals with MEN1. Not only will this allow novel insight into MEN1-related tumour formation and the identification of potential therapeutic targets, it will provide a unique resource for identifying and evaluating new treatments in downstream drug-discovery studies. In the longer term, these studies aim to lay the foundation for treatments aimed at tumour prevention in individuals with MEN1.

More About Paul

Paul undertook his medical training in Edinburgh and Oxford. His main research interests are in understanding the molecular and genetic basis of endocrine tumour formation. He has a particular clinical and research interest in Multiple Endocrine Neoplasia type 1 (MEN1) and Neuroendocrine tumours (NETs). Having recently relocated to Dundee, he is now establishing a program of work, which not only focuses on understanding why individuals develop endocrine tumours, but also on identifying new treatments.

Paul said, ‘I am delighted to have been successful in obtaining an AMEND Research Award. This award will play an important role in establishing a new avenue of research in the MEN1 field. Such novel approaches are essential to making progress. I hope this award will contribute to our understanding of why individuals with MEN1 develop pancreatic endocrine tumours, and in the longer term provide a foundation on which to identify new treatments.’