Prostate Cancer Research Team at the PGJCCR 

The Movember-Prostate Cancer UK Centre of Excellence Programme (FASTMAN) is a collaboration between the Prostate Cancer Research Group at QUB and Cancer Research UK (CRUK) Manchester Institute. The FASTMAN program in led by Professors Joe O’Sullivan and Suneil Jain in partnership with Professor Kevin Prise, Dr Simon McDade, and Dr Melissa LaBonte-Wilson and collaborates with the Northern Ireland Biobank  (NIB), and the Precision Medicine Centre (PMC), Northern Ireland Clinical Trials Network (NICTN) and Almac Diagnostic Services. 

Together, we have developed the world’s largest gene expression dataset for localised prostate cancer treated with radiotherapy, which has been utilised to develop /validate several novel prognostic biomarkers. We established a research procedural clinic at Belfast Health and Social Care Trust (BHSCT), enabling prospective longitudinal sample collection from patients with locally advanced prostate cancer (LAPC), before and during treatment with hormone therapy, radiotherapy and novel systemic therapies.

This has supported the delivery of successful innovative radiotherapy trials aimed at maximising efficacy and reducing radiation-induced toxicity and generation of novel human and murine primary cell lines for pre-clinical discovery research. Importantly, this clinical research platform, coupled with our world-leading pre-clinical drug-radiotherapy combination research has informed development and delivery of novel clinical trials (ADRRAD and  ASTRAD) and Prostate Cancer UK (PCUK) research funding for pre-clinical translational studies of novel therapeutic interventions (McDade, LaBonte-Wilson, Coulter).

Pictured above: Drs Simon McDade & Melissa LaBonte-Wilson

Modelling the biological effectiveness of these approaches to minimise toxicity is an area that is a key focus underpinning future trials and studies (Dr Karl Butterworth, Prof. Karen McCloskey and UKRI Future Leader Fellow, Dr Stephen McMahon).

Dr Emma Allott uses a combination of approaches to understand the links between lifestyle, inflammation and prostate cancer severity and progression (see Student Corner), and link the environment with response to disease and treatment. At a cellular level, the team of Dr Emma Evergren works towards discovering molecular mechanisms that affect cancer cell nutrient acquisition and stress responses, for example, which will lead into a deeper understanding of their survival strategies and responses to treatment. Dr Sarah Maguire’s group looks deeper into molecular aspects of cancer, using genomics and cancer-related bioinformatics, to investigate the extent to which somatic mutations in non-coding regions of the genome can drive prostate cancer development and progression.

(by Dr Melissa LaBonte-Wilson and Dr Cristina Branco)

Prostate cancer is a heterogeneous disease that is often made up of multiple tumour regions that have distinct topographical, morphological, genetic and epigenetic characteristics.  These variations lead to differences in patient prognosis. The different types of heterogeneity are shown in the table below.

Androgen Receptor (AR) are activated by androgens, and typically these receptors are expressed at high levels in malignant prostate cells, which makes them proliferate faster.

Depriving prostate tumour cells of androgens by Androgen Deprivation Therapy (ADT) such as Enzalutamide, is a mainstay of therapy for patients with advanced disease. Although initially effective in controlling disease, prostate cancer adapts to the loss of androgen signaling, and becomes less sensitive to ADT; this signals a transition towards an incurable prostate cancer state and therefore is an area of unmet clinical need – identifying therapeutic options for when ADT no longer works.

But there is currently increasing awareness that AR is also expressed in other cell types within the tumour. Our work demonstrates that the vascular endothelial cells (VECs) lining the blood vessels supplying blood to the prostate gland also express AR, and we have found that treatment of VECs with Enzalutamide results in the death of these cells and reduces supply of nutrients and oxygen, leading to a low oxygen state termed hypoxia.

Our work has shown that these tumours that become hypoxic in response to Enzalutamide-dramatically increasing the formation of new blood vessels to compensate and sustain the prostate tumour growth. As a result, the tumours become less sensitive to Enzalutamide treatment and the tumour growth accelerates.

We have been awarded a BBSRC CAST PhD studentship to develop these studies, and support research into hypoxia, tumour progression and therapeutic alternatives.

Our current research project focuses on therapeutic targeting of the adaptative changes that drive the resulting Enzalutamide treatment-induced hypoxia that promotes resistance. We have identified two biologically active factors that are induced under Enzalutamide treatment and hypoxia in PTEN-deficient prostate cancer and drive the resistant phenotype. These factors can be therapeutically inhibited with clinic-ready interventions to disrupt their effects within prostate cancer and restore the tumours sensitivity to both Enzalutamide-sensitive and resistant disease.

This research will yield important insights into how these interventions could be best used for prostate cancer patients within the clinic. We will provide high-level validation in clinically-relevant models of using an intervention targeting the two biologically active factors as a means to either prolong the magnitude and duration of benefit of ADT in patients or alternatively to potentially restore tumour control in patients with ADT has failed to work.