Irish Association For Cancer Research Meeting 2017

Irish Association for Cancer Research – Annual Meeting takes place at Newpark Hotel, Kilkenny on Thursday 23 and Friday 24 February 2017.

MCT cancer researchers secured oral presentations at different sessions. Prof Ray Stallings is a guest speaker at the Plenary Session focused on challenges in childhood cancers. He will be discussing ‘Modulation of neuroblastoma phenotype with epigenetically regulated miRNAs’.

Stephanie Annett will be giving a talk ‘FKBPL as a novel prognostic biomarker and therapeutic agent in high-grade serous ovarian cancer’ at Proffered Paper Session on Thursday morning. Two Irish Cancer Society funded PhD students will be discussing their findings at the Irish Cancer Society Scholar and Fellow Presentation session. Louise Walsh – ‘RNA sequencing identifies bromodomain proteins as a therapeutic strategy for invasive lobular carcinoma’ and Brian Mooney – ‘Expression of the cocaine- and amphetamine-regulated transcript recruits BAF chromatin remodelling complexes to the estrogen receptor’.

Good luck to our presenters!

Olga Piskareva

 

 

Diagnostic gene sequencing in adults with epilepsy and intellectual disability

MCT Research Talks – 20th February 2017

Sinead Heavin reports

Sinead Heavin, PhD Post-Doctoral Researcher

Epilepsy is a common neurological disorder that affects ~40,000 people in Ireland. There are many different types of seizures which are caused by uncontrolled electrical impulses in the brain. Anti-epileptic drugs control seizures for ~50% of people with epilepsy but up to ~30% of patients remain uncontrolled despite treatment with multiple drugs. Epilepsy is caused by a number of factors include stroke, trauma and infections. However, more recently we have learned that epilepsy can be caused by genetic mutations. Some epilepsies are heritable while others arise de-novo. Many patients with an intellectual disability (ID) also have epilepsy. Many of these patients lack a specific diagnosis due to limited testing and available investigations. We sequenced a cohort of 99 adult patients with epilepsy and ID on a custom gene panel of ~150 genes. A likely pathogenic variant was identified in 20 patients in 19 different genes, including SCN1A, DCX and DEPDC5, well-known epilepsy genes. Furthermore, we identified copy number variants in two patients which are likely causative. Further work is needed to investigate the phenotype-genotype correlations identified in this study and any potential treatment options that may arise.

MCT researchers shed light on the ancestry of the Irish Travellers from the perspective of DNA

Edmund Gilbert reports

A new study, led by Prof. Gianpiero Cavalleri at MCT and Prof. Jim Wilson at the University of Edinburgh, has examined the population history of the Irish Travellers and has confirmed that the Irish Travellers share a common Irish origin with the settled Irish population. The work has also for the first time estimated the date which this divergence occurred.

A roadside camp in County Mayo 1972. Courtesy of George Gmelch

The Irish Travellers are a small nomadic population, making up about 0.6% of the total population on the island of Ireland, or between 29,000 and 40,000 individuals. Within the population cousin marriages (consanguineous marriages) are common, and the population is socially isolated from the surrounding settled Irish population.
The researchers, who also include MCT PhD student Edmund Gilbert, Shai Carmi of the Hebrew University of Jerusalem, and Sean Ennis of University College Dublin, used SNP-array based genotype data to compare the population genetics of the Irish Travellers to neighbouring Irish and British populations, as well as world-wide groups and European Roma Gypsies.
The study found that although the Irish Travellers were genetic closest to the settled Irish population, they showed significant differences. The study also confirmed the lack of recent shared genetic ancestry between the Irish Travellers and Roma Gypsies. The Irish Travellers, therefore, represent a subset of Irish genetic diversity, and the significant differences can be attributed to genetic drift, brought on by hundreds of years of genetic isolation and a decreasing population size. The analysis showed Irish Travellers also exhibit within-population sub-structure with four apparently distinct groups emerging, and interestingly these groups mirror different forms of the Shelta language and sociological groups within the Irish Travellers.

Galway John Ward making tinware and Galway 1971. Courtesy of George Gmelch

The dating of the origin of the Irish Travellers is of considerable interest, but this is a distinct date from the genetic origins of each population. This study has estimated a time of genetic divergence of the Irish Travellers and the settled Irish population using genomic tracts of shared identity. This method estimated the divergence to about 12 generations (360 years) ago, which is far older than common belief that the Irish Traveller population arose from the time of the Great Famine. The size of the dataset limited the authors to exploring the relatively simple model of one divergence event, future work is required to expand the study to explore more complex demographic models. The Irish Traveller population was shown to have high proportions of the genome where both maternal and paternal copies are identical, at similar levels to other consanguineous populations around the world.
The research was also welcomed by author and Traveller activist, Michael McDonagh said, “As a Traveller who has spoken on the history and identity of Irish Travellers to many groups ranging from children to academics, you sometimes rely on anecdotal information in trying to put across a serious message about Irish Traveller history. I am delighted that now we have qualified evidence that substantiates the argument I have made for many years, which is that Travellers did not descend from the Famine in Ireland. This research allows us to bring Irish Traveller history back many and gives us a factual identity.”

Kay McKeon

8 February 2017

An informal, private reception was held in the College for Kay McKeon on Wednesday, 8th February, to mark her retirement and contribution to RCSI after 39 years.

Kay joined Clinical Pharmacology in 1978 and with Prof. Kevin O’Malley was responsible for commissioning the then ‘new’ laboratories. She continued to play a fundamental role in developing Clinical Pharmacology’s laboratories and building the department’s reputation through the 1980s and 1990s into RCSI’s premier research department.

She played a central role in assisting Kevin O’Malley’s successor, Prof. Des Fitzgerald, in securing RCSI’s first large HEA-PRTLI and SFI grants, working long hours with the intricate details and logistics for such applications.

During this period, Kay was seconded to oversee the development of the RCSI Centre for Human Proteomics, before returning to base and seeing in another period of change on the departure of Prof. Fitzgerald and formation of Molecular & Cellular Therapeutics (MCT) from the Departments of Biochemistry and Clinical Pharmacology under Profs. David Croke and John Waddington as HODs; she played a key role in the management of MCT as a member of it’s Executive.

At a more personal level, Kay was someone who carried out her responsibilities in a genuinely supportive and politically astute manner; many appreciated her sensitivity, in assisting all ‘new staff’ settle in and in maintained balance and stability in overseeing laboratories with up to 100 staff.

Yet in addition to this, Kay also found the time to contribute more broadly to RCSI, particularly its philanthropic activities, for example, the Old Folks Christmas Lunch for those living in the vicinity of the College and related activities; an all-too-rare rare combination of professionalism and altruism.

An important part of what Clinical Pharmacology and MCT has achieved serves as her legacy to the College, in making MCT what it is today and the entity that Prof. Tracy Robson has recently inherited.

Hebrews 6 (10 … 19): ‘For God would not be so unjust as to forget all that you did for love of his name, when you rendered service to his people, as you still do … It is like an anchor for our lives, an anchor safe and sure’.

Kay has been an ‘anchor safe and sure’ across four decades. We thank you, Kay, for everything you’ve done for Clinical Pharmacology, MCT, RCSI and the community at large and wish you well for the future.

RCSI and ALMAC Discovery Partnership to Target the Root of Cancer: Cancer Stem Cells

A New Year…and a new challenge for MCT postdoctoral researcher Gillian Moore 

Between the post-Christmas blues, cold days and that painful wait for the next pay day, January can be a pretty long and gruelling month. This year, deviating from the norm, my January kicked off to a great start with my eagerly awaited move to RCSI. Before Christmas I was delighted to find out that I would be working alongside Prof. Tracy Robson in the Department of MCT and I’m really excited for 2017, and the new opportunities and challenges this postdoctoral research position has to offer.
An ongoing research collaboration between the Robson research group and leading oncology pharmaceutical company, ALMAC Discovery, resulted in the development of ALM201, an anti-cancer peptide-based drug currently in Phase I clinical trial for patients with solid tumours. ALM201 is structurally based on the naturally occurring protein, FKBPL. FKBPL and its peptide-derivative, ALM201, have demonstrated potent anti-angiogenic properties, and notably, a unique ability to target cancer stem cells. Targeting of cancer stem cells has arguably become the Holy Grail of cancer therapy in recent years. Within the mass of every tumour there is a subpopulation of cancer cells with the ability to self-regenerate. It is this cell population that are responsible for the initiation and propagation of a tumour, and recurrence of disease following resistance to chemo and/or radiotherapy. If we can robustly target the bulk of the tumour in addition to any residual cancer stem cells then we can potentially circumvent progression and indeed recurrence of disease.

Left to right: Dr Graham Cotton, Senior R&D Group Leader, Almac Discovery; Prof Tim Harrison, Vice President Discovery Chemistry, Almac Discovery; Prof Tracy Robson, Head of Molecular & Cellular Therapeutics, RCSI; Dr Gillian Moore, postdoctoral researcher (Robson Group); Seamus Browne, RCSI Head of Industry Partnerships; Dr Stephanie Annett, postdoctoral researcher (Robson Group).

Ovarian cancer is one of the top ten most common cancers in women and is associated with a poor prognosis, primarily due to the late presentation of disease. In the coming months, the next stage in the clinical trial of ALM201 will involve the treatment of a cohort of ovarian cancer patients. Recent, unpublished preclinical data in the Robson group has indicated promising anti-cancer stem cell efficacy of ALM201 in the ovarian cancer setting. I am interested in understanding the molecular mechanisms that underpin this observed anti-cancer stem cell activity of ALM201. A new phase of academic research funding from ALMAC Discovery will enable us to carry out this work. While the specific targeting of ovarian cancer stem cells is a relatively new research field, it has potential to provide much needed alternate treatment options for this aggressive tumour type and may have implications for other malignancies.

It’s great to be part of MCT at RCSI and I’m looking forward to sharing our research findings as the project develops.

The Immune-Clock laboratory of Dr. Annie Curtis, a recent recruit to RCSI

MCT Research Talks – 30th January 2017

Last week’s departmental talks encompassed a Deep Dive into Clock biology in Macrophages affecting the Inflammatory Response. This area is the focus of the Immune-Clock laboratory of Dr. Annie Curtis, a recent recruit to RCSI.

Jamie Early, my PhD student

Jamie Early (PhD student of the Curtis Lab) currently residing in the Luke O’Neill Laboratory presented his findings on the role of the circadian clock in suppressing inflammation in macrophages and if the anti-oxidant transcription factor and redox sensor NRF2 plays a role. His talk was titled ‘The macrophage clock is a key controller of the anti-oxidant and inflammatory response via the transcription factor Nrf2’.

Second up, we had Mariana Cervantes (PhD student and visiting scientist from the Instituto Politecnico Nacional (IPN) in Mexico) present her talk titled ‘The macrophage clock is having a profound impact on mitochondrial dynamics- what are the implications for inflammation?’

Mariana Cervantes

Mariana is interested in how mitochondria alter their morphology, either fusing together to form networks or fragmenting into smaller units termed fission. She is trying to uncover if the clock is regulating this process and if so what are the implications for the inflammatory response.

This work is part of a collaboration between RCSI and  Luke O’Neill laboratory at TCD and is funded through Science Foundation Ireland

A pharmacogenomic exploration of adverse drug reactions in epilepsy (PGXOME)

For most people with epilepsy, long term treatment with anti-epileptic drugs (AEDs) are necessary to prevent the seizure, and 40% do not respond to the first line of AED, leading to an often lifelong odyssey of trial and error towards effective treatment that is often not found. Epilepsy is primarily treated using AEDs, but these are associated with a considerable risk for adverse drug reactions (ADRs), some of which have been shown to have a genetic predisposition. For example, the genetic variant HLA-A*3101 is a common risk factor for rash and severe blistering skin reactions with the drug carbamazepine (Tegretol) in Europeans. However there are few other predictors of some more common ADRs.

Dr. Mark McCormack

The EpiPGX Consortium was established to identify genetic biomarkers of epilepsy treatment response from patient centres across Europe. The EpiPGX Consortium has generated genetic profiles on over 8000 patients with matching detailed drug response and medical histories. In order to investigate the links between genetic profiles and ADRs in epilepsy, Dr. Mark McCormack will travel to UMC Utrecht, the Netherlands for one year on a  Marie-Skłodowska-Curie Fellowship from the European Commission.

The aim of this fellowship is to identify clinically useful genetic variants to predict adverse reactions to AEDs. This will help optimize personalized treatment, limit the trial and error approach of AED choice, and thus improve medication safety and quality of life in epilepsy.

RDS Primary Science Fair

Dr. Maria Morgan reports

On the 12th January 2017 I had the pleasure of attending the RDS Primary Science Fair which runs alongside the BT Young Scientist and Technology Exhibition. Although given the title of ‘Head Judge’ the Fair is non-competitive and provides a platform for showcasing STEM investigations (science, technology, engineering and maths) undertaken by primary school classes across Ireland.

Judges briefing at the RDS Primary Science Fair

Children exhibited their whole-class projects which included topics ranging from ‘How can we assist the declining bee population in our local area?’ to ‘Ambidextrous! Can I train my other hand?’. One of my favourites was ‘Why do we like Pink Lady apples so much?’ which demonstrated higher levels of sugar in Pink Ladies compared to other apple varieties. At another stand I was given the opportunity to have my lung capacity measured using a 5L water cooler bottle and some garden tubing (well how could I say no!). It’s such a privilege to attend the Fair each year where the positivity and enthusiasm for science means you come away with a feel-good scientific glow and a reassurance that the future of STEM in Ireland is in excellent little hands!
For more information on the RDS Primary Science Fair go to: www.rds.ie/Ireland-s-Philanthropic-Society/Our-Work/Projects/RDS-Primary-Science-Fair#sthash.z8tSvgG1.dpuf

Microcalcifications in breast cancer: Exploring their molecular formation and biological significance

MCT Research Talks – 23th January 2017

Survival rates for breast cancer have risen significantly over the past few decades, in large part due to a considerable increase in the number of tumours detected via mammography at an early, more easily-treated stage. The presence of microcalcifications on a mammogram constitutes an important diagnostic clue to radiographers, with approximately 30% of invasive breast tumours and up to 90% of cases of ductal carcinoma in situ (DCIS) being detected by the presence of calcifications. Some studies have also suggested that the presence of calcifications may act as a prognostic factor, as patients presenting with breast tumours with associated calcifications have a worse prognosis than those without.
Despite their importance in breast cancer diagnosis, the exact mechanism by which microcalcifications are formed remains largely unexplored. Our group previously established the first in vitro model of mammary cell microcalcification (1) which we have recently extended to the human the breast cancer cell line MDA-MB-231. When cultured with a cocktail of osteogenic-reagents for a prolonged period, these cells produce deposits of calcium phosphate.

Figure 1. Alizarin Red S stained MDA-MB-231 cell monolayer, grown in DMEM (Control) or DMEM supplemented with osteogenic cocktail and dexamethasone (OC+Dex). Red staining indicates presence of calcified deposits.

Using a combination of histological staining, quantitative measurement of calcium content, alkaline phosphatase activity and analysis of gene expression, we can monitor the changes in cell phenotype leading to onset of mineralisation. The nature of our model allows for easy manipulation of cell culturing conditions and by adding various inhibitory compounds or cytokines to our culture media, we can identify the key pathways and targets necessary for calcification production. In doing so, we hope to build up a comprehensive understanding of the cellular and molecular basis underlying the formation of these important diagnostic clues.

Recommended reading:

Cox RF, Hernandez-Santana A, Ramdass S, McMahon G, Harmey JH, Morgan MP.  Microcalcifications in breast cancer: novel insights into the molecular mechanism and functional consequence of mammary mineralisation. Br J Cancer. 106(3):525-37 PMID: 22233923 (Jan 2012)

Shane O’Grady, Maria Morgan

The role of the anorectic neuropeptide CART in breast cancer

MCT Research Talks – 16th January 2017

Breast cancer currently affects 1 in 8 women in Ireland, with over 3000 reported cases each year. The most common subtype of breast cancer, known as Estrogen Receptor positive (ER+) breast cancer, accounts for roughly 70% of all breast cancers diagnosed. The most common drug used to treat this disease (Tamoxifen) works by preventing estrogen from driving the growth of the cancer cells, however, roughly 1 in 3 women will be resistant to tamoxifen treatment, highlighting the need for further research into this field. A number of years ago, though mining of publically available datasets, we identified a gene known as CART to be a marker of poor prognosis in ER+ breast cancer. CART (The Cocaine- and Amphetamine-Regulated Transcript) is a neuropeptide involved in processes such as feeding and drug reward. We have identified that high expression of CART in breast cancer patients correlates with poor overall survival, and also a poor response to tamoxifen. We also demonstrated that CART could influence the activity of ERα in a ligand-independent manner [1]. Our current research focuses on combining proteomic (mass-spectrometry) and transcriptomic (RNA-seq) approaches in order to fully understand the role CART plays in ER+ breast cancer. We aim to modulate the expression of these identified targets in order to investigate whether any of these targets could slow the growth of breast cancer cells in vitro. Combining these approaches, we hope to identify novel therapeutic opportunities for patients with ER+ breast cancer.

Recommended reading:

[1] DJ Brennan, DP O’Connor et al., The Cocaine- and Amphetamine-Regulated Transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer. Oncogene 2012, 31, 3483–3494; doi:10.1038/onc.2011.519

Brian Mooney, Darran O’Connor