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Cancer Research UK Cambridge Institute

 

Neal group

Urological research

We are a translational research group based in urological surgery with a focus on high risk prostate cancer and the androgen receptor.

Our translational research programme is linked tightly to our clinical practice. We have a large and robotic radical prostatectomy programme, from which we have developed a well-annotated bio-repository on almost 1,500 men. In addition, material and data from ProtecT (the largest ever surgical randomised controlled trial in prostate cancer), have led to important collaborations with Ros Eeles at the Institute of Cancer Research (ICR) and Doug Easton at the Strangeways Research Laboratory (Al Olama et al., Hum Mol Genet. 2013; 22: 408; Kote-Jarai et al., Hum Mol Genet. 2013; 22: 2520; Pooley et al., Hum Mol Genet. 2013; 22: 5056; Eeles et al., Nat Genet. 2013; 45: 385). We also have an ongoing collaboration with Ros Eeles (ICR), Colin Cooper (UEA), Doug Easton, and with Ultan McDermott and Mike Stratton (Wellcome Sanger Institute) to carry out next generation sequencing of prostate cancers: our first paper has been submitted. Our ability to contribute to this work, was dependent on a collaboration with pathology to ensure good tissue sampling (Warren et al., Prostate. 2013; 73: 194). We have also established a multi-disciplinary group involving medical and clinical oncology, radiology and pathology and now have a funded programme of work with Astra-Zeneca to study novel therapeutic agents in a ‘window’ trial design with biological end-points.

Main discoveries
1. The AR and hormone relapsed prostate cancer (HRPC)

Androgen receptor (AR) signalling is maintained in most men with high risk and hormone relapsed disease. Our goals are to novel signalling pathways that in combination will lead to more effective treatments. The AR remains the primary target for treatment and the rationale remains strong for better targeting of this pathway and to uncover biomarkers. We are working with human tissue wherever possible, but our portfolio now includes pre-clinical in vivo models, which will give us better information on how individual genes function throughout tumour development.

We have performed AR ChIP-seq in fresh tissue samples obtained from men undergoing prostate surgery to study the transcriptional activity of the AR in a variety of patients with different stages of disease (Sharma et al., Cancer Cell. 2013; 23: 35). This includes those with early, localised disease and in particular those with advanced castrate-resistant prostate cancer (CRPC). We have demonstrated clearly that that AR is re-programmed in advanced disease with increased signalling through STAT, E2F and MYC. We have identified a 16-gene signature which outperformed a larger in vitro-derived signature in clinical datasets, showing the importance of persistent AR signalling in CRPC and revealing potential targets which would otherwise not have been implicated in CRPC. Work is ongoing to translate this signature into an assay that can be used on blood or urine rather than tissue. As therapies are currently being developed to target c-MYC and STAT, this study may prompt additional combination trials whilst offering possible surrogate response markers (Sharma et al., Cancer Cell 2013; 23: 35).

Furthermore, this demonstration of the critical role of cellular context in the regulation of transcription factor target selection and gene regulation highlights a wider need to utilise clinical material for the study of oncogenic transcription factors. Another study is underway studying the role of two novel tyrosine kinases in advanced prostate cancer as well as determining the impact of the AR in the DNA damage response. We have also demonstrated that a G-quadruplex region exists in the promoter of the AR whose inhibition results in a dose dependent inhibition of AR transcriptional activity (Mitchell et al., Biochemistry. 2013; 52: 1429).

2. Studies on HES6

We have completed our work on HES6, which is a transcription co-factor best known for its role in fate decisions of certain stem cell lineages. Its expression is increased by c-Myc and the AR, and this creates an altered transcriptional environment where prostate cancer cell division and growth is maintained in the presence of an active AR but in the absence of ligand binding by dihydrotestosterone. We have shown that Hes6 is able, in isolation, to drive cell growth in an androgen deprived/castrate setting, and that this maintained proliferation occurs in the context of a transcriptionally active AR. We have also shown that cell cycle and metabolic networks are activated, including up-regulation of E2F family members, CDC2, UBE2C, CDC20, Aurora kinases, PLK1, Cyclins, AMACR, GDF15 and LDHA. We have shown by ChIPseq the cooperation between Hes6, E2F1 and the AR to maintain G1/S transition and cell proliferation. This publication is under review.

3. Novel Biomarkers

We have identified three new biomarkers. Peroxiredoxin-3 is highly over-expressed in prostate cancer and protects cells from oxidative stress, which may be an important precursor of early changes of cancer (Whitaker et al., Br J Cancer. 2013; 109: 983). We have also identified N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 (NAALADL2) as a diagnostic and prognostic biomarker in prostate cancer.  We have shown that NAALADL2 promotes an invasive and migratory phenotype (Whitaker et al., Oncogene. 2013; Epub 18 Nov) and can distinguish men who are more likely to relapse following surgery (Figure 1). This work is being combined with data on two members of the vaculoar protein sorting family that we have also identified as being diagnostic and prognostic, and is being performed as part of an on-going collaboration with Henrik Gronberg at the Karolinska Institute. In addition to looking at proteins we have also identified an RNA signature found in circulating blood that can identify patients with aggressive forms of cancer.

Figure 1. (a) Both panels: expression of NAALAD2 in prostate cancer showing staining of malignant glands and absent staining of benign glands. (b) Effect of strong staining of NAALAD2 in association with recurrence-free survival.

4. Studies on beta-arrestin1 (ARRB1)

ARRB1 plays a role in cancer progression and some tumours show elevated levels in the nucleus where it may regulate gene expression via epigenetic mechanisms. We have shown that ARRB1 contributes to a metabolic shift to aerobic glycolysis via regulation of HIF1A activity through regulation of SDHA and FH expression in prostate cancer cells. This is the first example of an endocytic adaptor protein regulating metabolic pathways and implicates ARRB1 as a potential tumour promoter. A paper is in revision.

 

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