About
101
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Introduction
My research involves using next-generation sequencing and functional proteomic approaches to identify targetable molecular alterations in solid tumours, and also those molecular alterations that contribute to cancer resistance to targeted therapies. My research also aims to determine if circulating DNA/CTCs can be used as a “liquid biopsy” in patients undergoing treatment, to monitor tumour biology and, in particular, changes in therapeutic targets over the course of time and treatment.
Research Experience
March 2012 - present
Royal College of Surgeons in Ireland
Position
- Senior post-doctoral researcher
Description
- My research uses NGS and functional proteomics to identify targetable molecular alterations in tumours, and also molecular alterations that contribute to cancer resistance to targeted therapies.
March 2010 - February 2012
Royal College of Surgeons in Ireland
Position
- Post-doctoral Reseacher
Description
- The project involved targeting PI3K, MAPK and IGF signalling pathways in breast cancer particularly in the context of resistance to HER2-targetted therapies such as Lapatinib and Trastuzumab.
August 2005 - December 2009
University College Dublin
Position
- Post-doctoral researcher
Description
- The project involved looking at the effect of dietary supplements on insulin resistance and atherosclerosis in both a human population and an animal model.
Education
December 2001 - December 2004
October 1996 - June 2000
Publications
Publications (101)
The proviral integration of Moloney virus (PIM) family of protein kinases are overexpressed in many haematological and solid tumours. PIM kinase expression is elevated in PI3K inhibitor-treated breast cancer samples, suggesting a major resistance pathway for PI3K inhibitors in breast cancer, potentially limiting their clinical utility. IBL-302 is a...
Background:
An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance.
Methods:
The aim of ou...
179
Background: Combinative inhibitors with multiple actions to target downstream effectors are good strategy to reduce resistance occurrence. This is a preclinical study to evaluate efficacy of Palbociclib (P; CDK4/6 inhibitor) in combination with either Gedatolisib (G; P13K/mTOR dual inhibitors) or PD0325901 (PD; MEK 1/2 inhibitor) in CRC cell mo...
Background
HER2 is overexpressed in 10-25% of gastric cancers (GCs). The association of PI3K pathway activating mutations with HER2 overexpression, or the impact of aberrant PI3K pathway signalling on response to trastuzumab (Tr) in GC has not been described. In HER2-positive breast cancer, targeting the PI3K pathway can overcome resistance to HER2...
The treatment landscape for metastatic melanoma has been revolutionised by the introduction of immunotherapy and targeted therapies. Despite these advances, some patients exhibit primary or acquired resistance to treatment. We present the case of a resected mucosal melanoma that on relapse underwent transformation to a dedifferentiated state. The r...
Divergent roles for androgen receptor (AR) in breast cancer have been reported. Following aromatase inhibitor (AI) treatment, the conversion of circulating androgens into estrogens can be diminished by >99%. We wished to establish whether the steroid environment can dictate the role of AR and the implications of this for subsequent therapy. This st...
Background:The phosphoinositide 3 kinase (PI3K) pathway is important in the oncogenic function of HER2. Aberrant activation of PI3K is implicated in resistance to trastuzumab and other HER2-targeted therapies and is frequent, with up to 22% of HER2 positive breast cancer having a PIK3CA mutation. Copanlisib is a pan-class 1 PI3K inhibitor administe...
Introduction:
The microenvironment plays a major role in the survival of Chronic Lymphocytic Leukaemia (CLL) cells by promoting CLL cell growth and drug resistance. The traffic of CLL cells that involve migration from the blood and adhesion to the high endothelial venules (HEVs) facilitates the homing of lymphocytes in the lymph nodes to protect CL...
Background
The Insulin-like growth factor (IGF) pathway plays a role in tumour development and progression. In vivo, IGF1 activity is regulated by the IGF binding proteins (IGFBPs). IGFBP4 inhibits the activity of IGF1 but proteolytic cleavage by pregnancy-associated plasma protein-A (PAPP-A) releases active IGF1. A modified IGFBP4, dBP4, which was...
Background/aims:
Uveal melanoma (UM) is a highly aggressive malignancy and presents a clinically significant unmet need in cancer therapeutics. The aim of this study was to identify previously unreported mutations in UM among an Irish cohort of patients which may have potential clinical relevance.
Methods:
DNA was extracted from 36 intraocular m...
We designed and synthesised a series of novel chalcones, incorporating the heterocyclic framework of 2,2-dimethyl-2,3-dihydro-4(1H)-quinolinone, which was prepared via Sonogashira coupling of a substituted orthoaniline under aqueous conditions using Pd catalysis followed by acid-mediated cyclisation. The compounds were screened against the NCI-N87...
Breast cancer is the leading cause of cancer related deaths in women worldwide and is classified into subtypes based on the cancer’s receptor status. Of these subtypes, those expressing the human epidermal growth factor receptor 2 (HER2) receptor were traditionally associated with poor prognosis. Several advances have been made in the treatment of...
Adjusted p-values for all the Tukey Honest Significant Difference tests and ANOVA models across the HER2 and the all the breast cancer cell lines.
(CSV)
The initial screen of 28 genes from DNA extracted from the FFPE tumour samples of 32 women with HER2-positive breast cancer.
(CSV)
The frequency of the 6 SNPs in the study population.
(CSV)
Background
Somatic mutations in the ERBB genes (epidermal growth factor receptor: EGFR, ERBB2, ERBB3, ERBB4) promote oncogenesis and lapatinib resistance in metastatic HER2+ (human epidermal growth factor-like receptor 2) breast cancer in vitro. Our study aimed to determine the frequency of mutations in four genes: EGFR, ERBB2, ERBB3 and ERBB4 and...
Supplementary_material – Supplemental material for Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer
Introduction
Inhibitors of poly(ADP-ribose) polymerase (PARP) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, resistance to PARP inhibitors (PARPi) is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without re...
The EGFR-T790M somatic mutation is the most common mechanism of resistance to Tyrosine Kinase Inhibitors (TKI) in non-small cell lung cancer. Patients with advanced disease are not always amenable to repeat biopsy for further molecular analysis. Developing non-invasive methods to detect T790M in cell-free DNA (cfDNA), in the absence of tissue is be...
Background
The phosphoinositide 3 kinase (PI3K) pathway is important in the oncogenic function of HER2. Aberrent activation of PI3K is implicated in resistance to trastuzumab and other HER2-targeted therapies and is frequent, with up to 22% of HER2 positive breast cancer having a PIK3CA mutation. Copanlisib is a pan-class 1 PI3K inhibitor that show...
Background: CXCL16 is a pro-inflammatory chemokine associated with chemotaxis of CXCR6-expressing lymphocytes (T cells, NKT cells, NK cells) and the promotion of breast cancer cell proliferation, migration, and invasion . CXCL16 exists in a transmembrane or a cleaved, soluble form. There is limited clinically relevant data available on the CXCL16/C...
Background
The application of genomic technologies to patient tumor samples identified groups of signaling pathways which acquire activating mutations. Some cancers are dependent on these mutations and the aberrant proteins resulting from these mutations can be targeted by novel drugs which can eradicate the cancer.
Methods
We used www.cbioportal....
Background
The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase...
Purpose
The MEK/MAPK pathway is commonly activated in HER2-positive breast cancer, but little investigation of targeting this pathway has been undertaken. Here we present the results of an in vitro preclinical evaluation of refametinib, an allosteric MEK1/2 inhibitor, in HER2-positive breast cancer cell lines including models of acquired resistance...
BACKGROUND: We have shown that (EGFR, 2, and 4) germline single nucleotide polymorphisms (SNPs) have a negative impact on the outcome of trastuzumab treated HER2-positive breast cancer (BC) patients. Currently TCH (taxotere, platinum and trastuzumab) based therapy is used to treat early stage HER2-positive BC. We investigate the importance of germl...
9032
Background: The EGFR-T790M somatic mutation is the most common mechanism of resistance to Tyrosine Kinase Inhibitors (TKI) in NSCLC. However patients with advanced disease are not always amenable to repeat biopsy for further molecular analysis. Developing non-invasive methods to detect T790M in cell-free DNA (cfDNA), in the absence of tissue i...
3616
Background: Locally advanced rectal cancer, LARC (T3/4 and/or N+) is currently treated with neoadjuvant chemoradiotherapy (NACRT), however clinicopathological response is variable. Monitoring clonal evolution in response to NACRT may identify mutations driving therapeutic resistance or tumor growth after treatment. Methods: Fresh-frozen pre- a...
583
Background: In the TCHL trial (NCT01485926) 78 women with HER2-positive breast cancer (BC) underwent neo-adjuvant treatment with either TCH (Docetaxel, Carboplatin, Trastuzumab) or TCHL (TCH + Lapatinib) therapy. Of the 78 patients, 24 consented to an optional on-treatment biopsy 20 days after 1 cycle of therapy. We analysed the impact of tumou...
11587
Background: The advent of immunotherapy represents a paradigm shift in the treatment of NSCLC compared to conventional chemotherapy. Recent studies have shown higher mts burden assessed by exome sequencing are associated with improved objective response and clinical benefit. We performed this study to evaluate the impact of ML assessment by L...
Background:
Trastuzumab treatment for women with HER2-positive breast cancer (BC) resulted in the significant improvement of both relapse free survival (RFS) and overall survival (OS). However, many women who are classified as HER2-positive do not respond. Many studies have focused on the role of somatic mutations rather than germline polymorphism...
Objective
The mitochondrial apoptosis pathway is controlled by an interaction of multiple BCL-2 family proteins, and plays a key role in tumour progression and therapy responses. We assessed the prognostic potential of an experimentally validated, mathematical model of BCL-2 protein interactions (DR_MOMP) in patients with stage III colorectal cance...
Purpose: Apoptosis is essential for chemotherapy responses. In this discovery and validation study, we evaluated the suitability of a mathematical model of apoptosis execution (APOPTO-CELL) as a stand-alone signature and as a constituent of further refined prognostic stratification tools. Experimental Design: Apoptosis competency of primary tumor s...
Background: TCGA analysis revealed that somatic EGFR, ERBB2, ERBB3 and ERBB4 mutations (ERBB family mutations) occur alone or co-occur with somatic PIK3CA mutations in 19% of HER2-positive breast cancers. As ERBB family mutations can activate the AKT pathway it is likely that they have similar canonical signalling effects to PI3K pathway mutations....
Background: ‘TCHL’ an ICORG phase-II neo-adjuvant study in HER2+ve Breast cancer (BC) assessed the impact of TCH (Docetaxel, Carboplatin, Trastuzumab) versus TCHL (Docetaxel, Carboplatin, Trastuzumab, Lapatinib) in 78 patients. In these patients we determined the impact of total infiltrating lymphocytes (stromal and tumoral) (TIL) as a prognostic m...
Background: The success of PI3K targeted inhibition has been hampered by a high rate of drug resistance, which may be facilitated by MEK pathway signaling. As such, investigation of PI3K-MEK co-targeted inhibition is warranted. With high morbidity and mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung...
Background: Somatic mutations in the 4 HER family genes (EGFR, HER2, 3, 4) occur in HER2-positive breast cancer (HER2+ BC). (Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumors. Nature 2012;490(7418): 61-70.) We investigated their frequency in a large set of HER2+ BCs and their therapeutic relevance.
Methods: Tumors fr...
Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management....
615 Background: Whole genome sequencing of colorectal cancer (CRC) has identified common mutations that have been implicated in tumorigenesis. We investigated the association between genetic mutations in known cancer related signaling pathways, and clinicopathological variables in patients with CRC. Methods: DNA samples of patients with CRC were ge...
Approximately 20 % of human breast cancers (BC) overexpress HER2 protein, and HER2-positivity is associated with a worse prognosis. Although HER2-targeted therapies have significantly improved outcomes for HER2-positive BC patients, resistance to trastuzumab-based therapy remains a clinical problem. In order to better understand resistance to HER2-...
The PI3K pathway is a key mechanism of trastuzumab resistance, but early attempts to indirectly target this pathway with mTOR inhibitors have had limited success. We present the results of a preclinical study of the selective alpha/delta isoform dominant PI3K inhibitor BAY 80-6946 tested alone and in combination with HER2-targeted therapies in HER2...
Unlabelled:
In locally advanced rectal cancer, neoadjuvant chemoradiotherapy is performed prior to surgery to downstage the tumour. Thirty to 40 % of patients do not respond. Defects in apoptotic machinery lead to therapy resistance; however, to date, no study quantitatively assessed whether B cell lymphoma 2 (BCL2)-dependent regulation of mitocho...
Angiogenesis or new vessel formation is essential for tumour growth and progression. Therefore, targeting angiogenesis has been an attractive strategy in the treatment ofcancer. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody thattargets vascular endothelial growth factor-A (VEGF-A) - a key molecular player inangiogenesis. Bevacizum...
Locally advanced rectal cancer (LARC: T3/4 and/or node-positive) is treated with preoperative/neoadjuvant chemoradiotherapy (CRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and related pathways are implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic mutat...
Somatic mutations in BRAF occur in two thirds of cutaneous melanomas, leading to the activation of the RAF-MEK-ERK signalling pathway. Preclinical studies of BRAF mutations showed that inhibition of BRAF led to melanoma cell proliferation inhibition and apoptosis induction in vitro and blockade of melanoma xenograft growth in vivo. Clinical studies...
Background: Aberrant activity of the mitogen-activated protein kinase (MAPK) signalling pathway represents a critical factor in the initiation and development of melanoma. Activation can be the result of largely mutually exclusive somatic mutations of KIT, NRAS, or more frequently, BRAF(V600E). The FDA and EMA approval of a BRAF inhibitor (vemurafe...
3549
Background: Locally advanced rectal cancer, LARC (T3/4 and/or N+) is currently treated with pre-operative chemoradiotherapy (pCRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP-kinase (MAPK) and related pathways have been implicated in rectal cancer tumorigenesis. Here, we investigated the association between ge...
Triple-negative breast cancer (TNBC) is characterised by the absence of estrogen receptor (ER), progesterone receptor (PR) and the HER-2 receptor. TNBC is typically associated with a poor prognosis due to aggressive tumour phenotypes, partial response to chemotherapy, and current lack of clinically validated targeted therapies. Insulin-like growth...
Conjugated linoleic acid (CLA) is found naturally in meat and dairy products, and represents a potential therapeutic functional nutrient. However, given the discrepancies in isomer composition and concentration, controversy surrounds its proposed antidiabetic, antiobesity effects. This study focused on the effects of CLA-enriched beef (composed pre...
Schematic illustration of pathway extraction algorithm; data frame at right shows example network data file at each step of algorithm. The key goal of this algorithm is to assess a linked path of nodes (in this case A→B→C→D), to identify if an unbroken path of metabolite conversion can be traced from the first node to the last. Given a node of inte...
Results from sPLS of adipose tissue gene expression and components of recorded habitual diet. Diet-gene pairs passing the similarity threshold of 0.7 are shown.
(DOCX)
Paths detected by applying network analysis algorithm to test muscle tissue dataset (GEO accession GSE474).
(DOCX)
Diet-gene and phenotype-gene relationships, and modular partitioning mapped to the transcriptionally coordinated human metabolic network. Green nodes: dietary variables; yellow: lipid, fatty acid and apolipoprotein variables; red: inflammatory and oxidative stress markers; blue: genes (enzymes). Enzyme nodes are connected if they meet two condition...
Summary of plasma and urinary markers of metabolic health in the LIPGENE transcriptomic study cohort.
(DOCX)
Results from rCCA of adipose tissue gene expression and plasma fatty acids, lipids and apolipoproteins. Plasma marker-gene pairs passing the similarity threshold of 0.75 are shown.
(DOCX)
Significantly overrepresented Gene Ontology ‘biological process’ terms in the adipose tissue TC network modules. Top 10 terms for each module are shown.
(DOCX)
Summary of anthropometric characteristics and habitual dietary patterns in the LIPGENE transcriptomic study cohort.
(DOCX)
Results from rCCA of adipose tissue gene expression and plasma cytokines, IVGTT measurements, prostaglandin and urinary isoprostane. Plasma marker-gene pairs passing the similarity threshold of 0.7 are shown.
(DOCX)
Understanding the molecular link between diet and health is a key goal in nutritional systems biology. As an alternative to pathway analysis, we have developed a joint multivariate and network-based approach to analysis of a dataset of habitual dietary records, adipose tissue transcriptomics and comprehensive plasma marker profiles from human volun...
bi-directional GSEA script. R script used to carry out bi-directional gene set enrichment analysis. Adapted from gsealmPerm function in GSEAlm package [17].
Figure S1: Full GSEA results for high-CLA-diet effects in liver, muscle and adipose tissue. Heatmap showing bi-directional GSEA results for KEGG pathways in liver, muscle and adipose tissue.
Figure S1 legend. Descriptive legend for figure S1.
Currently, a number of bioinformatics methods are available to generate appropriate lists of genes from a microarray experiment. While these lists represent an accurate primary analysis of the data, fewer options exist to contextualise those lists. The development and validation of such methods is crucial to the wider application of microarray tech...
The WHO estimate that >1 x 10(6) deaths in Europe annually can be attributed to diseases related to excess body weight, and with the rising global obesity levels this death rate is set to drastically increase. Obesity plays a central role in the metabolic syndrome, a state of insulin resistance that predisposes patients to the development of CVD an...
Inter-organ proteomic analysis reveals insights into the molecular mechanisms underlying the anti-diabetic effects of cis-9, trans-11 conjugated linoleic acid in ob/ob mice - Volume 69 Issue OCE1 - V. Rungapamestry, B. De Roos, J. McMonagle, G. Rucklidge, M. Reid, G. Duncan, G. Horgan, A. P. Moloney, S. Toomey, H. M. Roche
cis-9, trans-11-Conjugated linoleic acid (c9 t11 CLA) exerts anti-diabetic effects by improving systemic insulin sensitivity and inflammation. Levels of CLA in beef can be increased by feeding cattle on pasture. This study aimed to explore the efficacy of a CLA-rich diet (0.6% w/w c9 t11 CLA), presented as beef enriched with CLA or beef supplemente...
The development of insulin resistance in the obese is associated with chronic, low-grade inflammation. We aimed to identify novel links between obesity, insulin resistance and the inflammatory response by comparing C57BL/6 with type I interleukin-1 receptor knockout (IL-1RI(-/-)) mice, which are protected against diet-induced insulin resistance. Mi...
Obese IL-1 receptor-I-deficient (IL-1RI−/−) mice are protected against diet-induced insulin resistance via a down-regulation of inflammation and oxidative stress in adipose tissue: a proteomics investigation - Volume 67 Issue OCE7 - V. Rungapamestry, B. De Roos, K. Ross, G. Rucklidge, M. Reid, G. Horgan, S. Toomey, J. Browne, C. Loscher, H. M. Roch...
Adipose tissue may be the source of insulin desensitizing proinflammatory molecules that predispose to insulin resistance. This study investigated whether dietary fatty acids could attenuate the proinflammatory insulin-resistant state in obese adipose tissue. The potential antidiabetic effect of cis-9, trans-11-conjugated linoleic acid (c9,t11-CLA)...
Much attention has focused on the therapeutic potential of conjugated linoleic acid with the most abundant isomers being cis-9,trans-11 conjugated linoleic acid and trans-10,cis-12 conjugated linoleic acid. Initial animal studies associated conjugated linoleic acid with beneficial health properties, such as reducing the risk of cancer, diabetes, at...
Conjugated linoleic acid (CLA) refers to a group of positional and geometric isomers of linoleic acid and has been shown to suppress the development of atherosclerosis in experimental models. However, the mechanism involved is unclear although it is believed it may act as a cyclooxygenase inhibitor or as an agonist of the nuclear receptors, peroxis...
Proteins secreted by activated platelets can adhere to the vessel wall and promote the development of atherosclerosis and thrombosis. Despite this biologic significance, however, the complement of proteins comprising the platelet releasate is largely unknown. Using a proteomics approach, we have identified more than 300 proteins released by human p...
Cyclooxygenase (COX) activity is induced in human atherosclerosis, and the products formed may modify the disease directly or through an effect on platelets. We examined the role of COX-1 and -2 on platelet vessel wall interactions and development of atherosclerosis in a murine model.
Apolipoprotein E-deficient (apoE-/-) mice fed a 1% cholesterol d...
Projects
Projects (2)
1. Determine frequency of ERBB-mutations in breast cancer
2. Identify in-vitro and in-vivo therapeutic strategies for treatment of ERBB-gene mutated cancers
