TRRAP & BRAIN CANCER · Targeted inhibition of TRRAP as a strategy against aggressive brain cancer

Periodic Report Summary 1 - TRRAP & BRAIN CANCER (Targeted inhibition of TRRAP as a strategy against aggressive brain cancer)

1. Publishable summary Brain cancer is a worldwide problem that remains poorly understood. For example, every year, ~6,000 cases of brain cancer are newly diagnosed in the UK alone and ~3,700 people die from this devastating disease. Many brain cancer deaths are caused by the most aggressive brain tumour, Glioblastoma multiforme (GBM). GBM is the most frequent primary brain tumour in adults and patients have an extremely poor prognosis and complete surgical removal of the cancer is often impossible. Despite chemo- and irradiation therapy, the median patient survival time is only 12-17 months. This is a devastating fact for the patients who face a potentially incurable disease and the patient’s families who often have to rearrange their lives to become carers. Brain tumours are very difficult to treat due to their high complexity resulting from molecular and cellular diversity within a single brain tumour (intra-tumour heterogeneity), tumour heterogeneity among individual patients (inter-tumour heterogeneity), tumour invasion (infiltration of tumour cells into healthy brain tissue), and resistance of certain tumour cells to chemotherapy and radiation therapy. One major breakthrough in recent years has been the characterization of a subpopulation of undifferentiated, therapy-evading tumour cells, termed brain tumour stem cells (BTSCs). BTSCs do represent the most dangerous cellular subpopulation in a brain cancer by fuelling its’ development and progression. Unlike differentiated cells of the tumour bulk, BTSCs can potentially generate tumours from few if not a single cell. They are thought to possess the abilities to migrate within the brain, to switch on cellular repair mechanisms in response to DNA-damaging therapies, and to expand their numbers causing tumour relapse after surgical intervention. Therefore, future treatment efforts need to target these malignant capacities of BTSCs and improved treatment options, including new combination therapies against all cellular components of brain tumours, are urgently needed. Building on my expertise obtained during my postdoctoral studies in the P.G. Schultz laboratory at The Scripps Research Institute, La Jolla, USA, and with the help of the Marie Curie Career Integration Grant, I was able to develop an externally-funded research group at the University of Leeds (http://medhealth.leeds.ac.uk/profile/950/753/heiko_wurdak). Since starting as a tenure-track group leader in 2011, our research seeks to determine the specific role of proteins that may play a crucial role in aggressive brain cancer including transformation/transcription domain-associated protein (TRRAP). While this is basic science, we hope that our findings may be exploited for drug discovery and drug development strategies in the future. For example, a detailed molecular knowledge of TRRAP in the context of brain cancer will be required to develop novel TRRAP-inhibitory chemical agents and we are working towards bridging this critical knowledge gap.

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