February 2014

St Luke’s Medals Success for UCD Medicine

Sat, 1 February 14 11:00

UCD Medicine was well represented at this year’s RAMI/St Luke’s Hospital scientific meeting which took place on Wednesday 29th January 2014 at the Royal College of Physicians in Ireland.  Assoc. Prof. Malcolm Kell (consultant surgeon at Mater Misericordiae University Hospital and UCD Associate Clinical Professor) delivered the 39th St Luke’s Lecture while Dr Maria Prencipe (Irish Cancer Sociert Research Fellow) won the highly competitive 11th St Luke's Young Investigator award.

St Luke’s Lecture & Medal

Assoc. Prof. Kell’s lecture entitled ‘Breast Cancer : From Halstead to Harney’ reviewed the developments in breast cancer care since the pioneering work of Dr. William Stewart Halstead who is credited with performing the first mastectomy.

The management of Breast cancer has changed dramatically since the early 1970s. Numerous studies have helped develop modern breast cancer surgery whereby conservative surgery is now the standard of care. Both the management of the breast and the axilla have evolved to not only achieve the best oncological outcomes but also limit patient morbidity from treatment. Breast reconstructive surgery is now routinely used to rebuild breasts after mastectomy and a range of techniques are now available to obtain the optimum results and also avoid potential problems associated with radiotherapy.

As our understanding of the pathogenesis of breast cancer has improved, we can now identify patients at risk and then offer genetic screening to high risk individuals. Once identified with a BRCA abnormality, patients can be radiologically screened and offered potential prophylactic measures to reduce the risk of developing cancer. Prophylactic mastectomy provides excellent risk reduction for high risk patients and novel tools are now available to measure patient quality of life after this prophylactic surgery.

Breast screening has been the model of cancer screening over the last 4 decades. However numerous controversies exist regarding the efficacy of mammographic screening. Recent evidence strongly supports mammographic screening when different screening studies are examined uniformly. The Irish Breastcheck program exemplifies best outcomes from screening, and data from the Irish program strongly supports breast cancer screening.

St Luke’s Young Investigators Award

Dr Maria Prencipe (Irish Cancer Society Research Fellow) took the top prize in the prestigious 11th St Luke’s Young Investigators Awards at the RAMI/St Luke’s Hospital symposium held in the Royal College of Physicians of Ireland.  Dr Prencipe’s research investigates building a pipeline for novel therapies in castrate-resistant prostate cancer (CRPC).

Commenting on the win Dr Prencipe said,

“I am delighted to win the 11th St Luke’s Young Investigators Award for my research that looks at the treatment of castrate-resistant prostate cancer (CRPC), which, despite the emergence of new treatments, is still challenging to treat.

“Defining the mechanism of resistance represents a key question facing clinicians and scientists, and we have been using a combination of transcriptomics (or genome-wide expression profiling) and bioinformatics analysis with much success. We have recently identified Serum Response Factor (SRF) as an important transcription factor in an in vitro model of CRPC. We investigated the relationships between SRF and androgen receptor (AR) in advanced prostate cancer, and a negative feedback loop was demonstrated, signifying the importance of SRF and CRPC and support SRF as a promising therapeutic target alone or in combination with current treatments.”

The St Luke’s Young Investigators Award, established in 2004, recognises young researchers in the field of clinical, basic or translational oncology research who are in their early years of research. The award is supported by the Royal Academy of Medicine in Ireland and St Luke’s Radiation Oncology Network, Dublin.

All four finalists in this year’s competition were Irish Cancer Society Research Fellows with two funded through the Movember Ireland initiative.  Commenting on the win, former UCD Professor of Surgery, Prof. John Fitzpatrick, Head of Research at the Irish Cancer Society said,

“We are incredibly proud of Dr Maria Prencipe and all the finalists who represent a cohort of future research leaders who will keep the field of cancer research vibrant with new ideas and a steadfast commitment to their field. That all four are Irish Cancer Society Research Fellows is a marvelous achievement for the Society. We congratulate Dr Maria Prencipe on her outstanding achievement winning the 11th St Luke’s Young Investigators Award, and encourage her to continue in her career to advance high-quality research in the area of prostate cancer in Ireland.”

Scientific Abstract

A new molecular target for castrate-resistant prostate cancer: negative feedback loop between SRF and AR

Maria Prencipe1, Gillian O’Hurley 2,3, Amanda O’Neill1, Dara Lundon1, Lan K. Nguyen4, Susie Boyce 1,5, Colm Morrissey6, Helmut Klocker7, Elaine W Kay8, William M. Gallagher 2,3, R William Watson1
1 UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, D4, Dublin, Ireland
2 OncoMark Limited, NovaUCD, Belfield Innovation Park, Belfield, D4, Dublin, Ireland
3 UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, D4, Dublin, Ireland
4 Systems Biology Ireland, University College Dublin, Belfield, D4, Dublin, Ireland
5 UCDSchoolof Mathematical Sciences, Dublin, Ireland
6 Department of Urology, Washington University, Seattle, Washington, USA
7 Department of Urology, Innsbruck Medical University, Anichstraße 35, Innsbruck, Austria
8 Department of Pathology, RCSI Education and Research Centre; Beaumont Hospital, Dublin, Ireland

 

While early detection of prostate cancer allows for curative therapies such as surgery and radiation treatments, patients with locally advanced and metastatic prostate cancer are treated with androgen ablation therapy. However, despite an initial response, the majority of men will progress to develop castrate-resistant prostate cancer (CRPC) which, despite the emergence of new treatments such as abiraterone acetate and MDV3100, is still challenging to treat. Therefore defining the mechanisms of resistance represents a key question facing clinicians and scientists. Using a combination of transcriptomics profiling and bioinformatics analysis, we have recently identified Serum Response Factor (SRF) as an important transcription factor in an in vitro model of CRPC. Since CRPC is associated with androgen receptor (AR) hypersensitivity and previous studies linked SRF with AR, we investigated the relationship between SRF and AR in advanced prostate cancer.

Luciferase reporter assays showed that DHT stimulation increased SRF transcriptional activity in both parental LNCaP cells and their castration-resistant Abl subline; with a 10 fold higher response in the latter. To investigate AR involvement in this process, AR expression was down-regulated using siRNA, resulting in the abrogation of SRF induction post-DHT. Moreover, DHT stimulation failed to induce SRF transcriptional activity in the AR-negative PC346 DCC cells. However, when AR was over-expressed in these cells, SRF induction post-DHT was restored.  To explore whether this was reciprocal, SRF was down-regulated by siRNA and AR transcriptional activity and protein expression were assessed. These experiments showed AR increased activity and expression following SRF knock-down, suggesting a negative feedback loop, which was confirmed by immunohistochemistry (IHC) in CRPC bone metastases (n=42), showing a negative association between SRF and AR positivity. This negative feedback loop was also supported by a computational model based on our experimental data.

We next assessed cell proliferation following SRF inhibition and demonstrated that SRF inhibition by siRNA or the small molecule inhibitor CCG-1423 was as effective as AR inhibition (siRNA and MDV3100) in decreasing cell proliferation. Moreover concomitant inhibition of AR and SRF showed a synergistic effect.

To confirm SRF relevance in clinical samples, we performed IHC staining for SRF on 94 primary tumours and 21 tumours from patients who received a transurethral resection of the prostate (TURP). This analysis showed that SRF nuclear staining was associated with castration-resistance with 95% of castration-resistant TURPs showing positive SRF staining versus only 50% of primary tumours. Moreover nuclear SRF expression in bone metastases in an independent cohort of 38 patients who died of CRPC, was shown to be an independent predictor of survival from diagnosis with (a) prostate cancer and (b) CRPC.

In conclusion our study shows evidence of a cross-talk between AR and SRF in advanced prostate cancer. At the core of this cross-talk a negative feedback loop between SRF and AR was demonstrated in vitro and in clinical samples as well as being supported by a computational model. These data demonstrate the importance of SRF in CRPC and support SRF as a promising therapeutic target alone or in combination with current treatments.