Cancer

The goal of all of the cancer research programmes at the NICB is to investigate the biology of cancer using a wide variety molecular biology, proteomic, and biochemical technologies applied to cancer tissue and biofluids in vivo and cancer cell models in culture. We aim to understand function of cellular proteins and pathways and to collaborate with clinicians in Dublin hospitals as well as nationally and internationally, and with industry to build better treatments and diagnostic approaches for cancer patients.

Research Areas

Principal Investigators

Prof. Martin Clynes

Dr. Paula Meleady

Dr. Michael Moriarty

This programme aims to better understand the molecular biology underlying the malignant behaviour of pancreatic cancer cells, with a particular focus on the proteome and its regulation by miRNAs. It also seeks to identify better blood biomarkers for pancreatic and colorectal cancers which might be used to give early warning that a particular treatment was ineffective. A further strand of our research uses our collection of unique multidrug-resistant cell lines to search for new potential therapeutic approaches for resistant cancers, including lung cancer. There is very close collaboration with the pancreatic cancer treatment group in St Vincent’s University Hospital and in radiobiology research with St. Luke’s hospital.

Publications

  1. Coleman O, Henry M, O’Neill F, Roche S, Swan N, Geoghegan J, Conlon K, McVey G, Moriarty M, Meleady P, Clynes M. Proteomic Analysis of Cell Lines and Primary Tumors in Pancreatic Cancer Identifies Proteins Expressed Only In Vitro and Only In Vivo. Pancreas. 2020 Sep;49(8):1109-1116. doi: 10.1097/MPA.0000000000001633.
  2. Roche S, O’Neill F, Murphy J, Swan N, Meiller J, Conlon NT, Geoghegan J, Conlon K, McDermott R, Rahman R, Toomey S, Straubinger NL, Straubinger RM, O’Connor R, McVey G, Moriarty M, Clynes M. Establishment and Characterisation by Expression Microarray of Patient-Derived Xenograft Panel of Human Pancreatic Adenocarcinoma Patients. Int J Mol Sci. 2020 Jan 31;21(3):962. doi: 10.3390/ijms21030962.
  3. Coleman O, Henry M, O’Neill F, Roche S, Swan N, Boyle L, Murphy J, Meiller J, Conlon NT, Geoghegan J, Conlon KC, Lynch V, Straubinger NL, Straubinger RM, McVey G, Moriarty M, Meleady P, Clynes M. A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts. Proteomes. 2018 Nov 6;6(4):45. doi: 10.3390/proteomes6040045.
  4. O’Sullivan D, Dowling P, Joyce H, McAuley E, McCann A, Henry M, McGovern B, Barham P, Kelleher FC, Murphy J, Kennedy S, Swan N, Moriarty M, Clynes M, Larkin A. A novel inhibitory anti-invasive MAb isolated using phenotypic screening highlights AnxA6 as a functionally relevant target protein in pancreatic cancer. Br J Cancer. 2017 Oct 24;117(9):1326-1335. doi: 10.1038/bjc.2017.306
  5. O’Connor R, O’Leary M, Ballot J, Collins CD, Kinsella P, Mager DE, Arnold RD, O’Driscoll L, Larkin A, Kennedy S, Fennelly D, Clynes M, Crown J. A phase I clinical and pharmacokinetic study of the multi-drug resistance protein-1 (MRP-1) inhibitor sulindac, in combination with epirubicin in patients with advanced cancer. Cancer Chemother Pharmacol. 2007 Jan;59(1):79-87. doi: 10.1007/s00280-006-0240-7
Research Group Members

Dr Fiona O’Neill (postdoctoral researcher)

Project: Pancreatic cancer transcriptomics, role of miRNA, blood biomarkers, radiobiology

Funder: Pancreatic Cancer Research Fund, UK and St Luke’s Institute for Cancer Research, Dublin

Dr Esen Eflogu (postdoctoral researcher)

Project: Proteomic analysis of pancreatic cancer

Funder: Irish Research Council

Taylor Jade Allen-Coyle (PhD student)

Project: Functional role of miRNAs in pancreatic cancer cells; Analysis of combinations of anticancer drugs

Funder: SFI/ SSPC, the SFI Research Centre for Pharmaceuticals

Principal Investigators

Assistant Prof Naomi Walsh
naomi.walsh@dcu.ie
+353 (0) 700 5912

The Walsh lab “Translational Cancer Genomics and 3D Organoid Research” group is focused on developing 3D cancer organoid models, which bridges the gap between 2D in vitro models and in vivo models. Organoids enable the study of how cells interact together in a tumour, their interaction with their environment, how gene mutations/SNPs impact on cancer development and the effect of drugs. This technology facilitates great potential for clinical applications including defining and validating genomic variants in cancerdrug testing to guide personalized therapy. My lab uses cancer genomics to understand the development, progression, therapeutic response and subsequent resistance of cancer. Genomic and functional next generation approaches to identify the biological mechanisms of genomic and transcriptomic diversity to develop prognostic/predictive signatures and therapeutic strategies.

Publications

  1. Nelson SR, Roche S, Cotter M, Garcia PA, Reitmeier D, Zollbrecht E, O’Neill F, Clynes M, Doolan P, Medha JP, Swan N, Larkin A, Walsh N. Genomic Profiling and Functional Analysis of let-7c miRNA-mRNA Interactions Identify SOX13 to Be Involved in Invasion and Progression of Pancreatic Cancer. J Oncol. 2020 Dec 24;2020:2951921. doi: 10.1155/2020/2951921. PMID: 33424970; PMCID: PMC7775161.
  2. Walsh N, Andrieu C, O’Donovan P, Quinn C, Maguire A, Furney SJ, Gullo G, Crown J. Whole-exome sequencing of long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer. Br J Cancer. 2020 Oct;123(8):1219-1222. doi: 10.1038/s41416-020-0999-z. Epub 2020 Jul 27. PMID: 32713940; PMCID: PMC7553955.
  3. Yuan F, Hung RJ, Walsh N, et al. Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk. Cancer Res. 2020 Sep 15;80(18):4004-4013. doi: 10.1158/0008-5472.CAN-20-0447. Epub 2020 Jul 8. PMID: 32641412; PMCID: PMC7861352.
  4. Nelson SR, Walsh N. Genetic Alterations Featuring Biological Models to Tailor Clinical Management of Pancreatic Cancer Patients. Cancers (Basel). 2020 May 14;12(5):1233. doi: 10.3390/cancers12051233. PMID: 32423157; PMCID: PMC7281628.
  5. Nelson SR, Zhang C, Roche S, O’Neill F, Swan N, Luo Y, Larkin A, Crown J, Walsh N. Modelling of pancreatic cancer biology: transcriptomic signature for 3D PDX-derived organoids and primary cell line organoid development. Sci Rep. 2020 Feb 17;10(1):2778. doi: 10.1038/s41598-020-59368-7. PMID: 32066753; PMCID: PMC7026166.
  6. Walsh N, Zhang H, Hyland PL, et al. Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer. J Natl Cancer Inst. 2019 Jun 1;111(6):557-567. doi: 10.1093/jnci/djy155. PMID: 30541042; PMCID: PMC6579744.
Research Group Members

Shannon Nelson (PhD Student)

Novel organoid models for the functional validation of pancreatic cancer genomic variants

My Ph.D. research has focused on the development of better, more reliable, tractable organoid models which will enable accelerated preclinical research for pancreatic cancer. Using these models, we aim to functionally assess genomic variants of the disease to help identify those at risk of developing it.

Funder: Science Foundation Ireland

Sara Noorani (PhD Student)

Targeted delivery of 5-FU to overcome cancer stem cell (CSC) drug resistance in pancreatic and upper gastric (GE) cancers

The aim of my Ph.D. research is to identify new precision 5-FU based chemo-strategies for the treatment of pancreatic and GE cancers by targeting CSCs in 3D organoid models

Funder: Pancreatic Cancer Research Fund

Letizia Palanga (PhD Student)

Microfluidic techniques to develop pre-clinical tumour-derived models for analysis of personalised therapies in uveal melanoma

My Ph.D. project focuses on the development of UM organoids to model disease progression and to screen specific drugs based on the genetic landscape and drug sensitive patterns of patients.

Funder: Irish Research Council-Enterprise Partnership CCRT

Jojanneke Stoof (PhD Student)

Genomic analysis and functional profiling of DNA repair in pancreatic cancer organoids for identification of targetable DNA damage repair defects

My Ph.D. project aims to identify targetable DNA damage repair defects in pancreatic ductal adenocarcinoma. It will do so by functional analysis of DNA repair proficiency in organoids, as well as by analysis of somatic and germline alteration in genes associated with DNA repair pathways.

Co-supervisor: Prof Maeve Lowery, Trinity College Dublin

Funder: EU Horizon 2020, MSCA-ITN-Precode

Charlotte Andrieu (PhD Student)

Bioinformatics and computational approaches to investigate predispositions in pancreatic cancer risk.

I joined Naomi Walsh research group in 2020 to study and analyse multiple layers of data of pancreatic cancer. My role is to identify genetic variants which have a key role in pancreatic cancer development, using sequencing data (RNA-seq data, epigenetic data from Cut&Run) from unique organoid models and cell line organoids with recapitulate the original tumour.

Funder: Science Foundation Ireland

Principal Investigators

Assistant Professor Alex J Eustace
alex.eustace@dcu.ie
01 700 7497

The aim of the research in the Eustace lab is to identify and understand the importance of both coding and ‘regulatory’ mutations which exist in a patient’s cancer and determine whether they play a role in predicting response to specific inhibitors in the clinic.

Publications

  1. Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer
    Oncogene Volume 39, Issue 14, 2 April 2020, Pages 3028-3040
    Kennedy SP, O’Neill, M, Cunningham D, Morris PG, Toomey S, Blanco-Aparicio C, Martinez S, Pastor J, Hennessy BT*, Eustace AJ*.
  2. Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer
    Ther Adv Med Oncol 2018, Vol. 10: 1–16
    Elster N, Toomey S, Fan Y, Cremona M, Morgan C, Weiner Gorzel K, Bhreathnach U, Milewska M, Murphy M, Madden SF, Naidoo J, Fay J, Kay EW, Carr A, Kennedy S, Furney S, Mezynski J, Breathhnach O, Morris P, Grogan L, Hill AD, Kennedy S, Crown J, Gallagher WM, Hennessy BT*, Eustace AJ*
  3. Development of a personalized therapeutic strategy for ERBB-gene-mutated cancers
    Ther Adv Med Oncol 2018, Vol. 10: 1–24
    Milewska M, Cremona M, Morgan C, O’Shea J, Carr A, Velanki SH, Hopkins AM, Toomey S, Madden SF, Hennessy BT*, Eustace AJ*.
  4. Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies
    Breast Cancer Research, 2017, 19:87
    Eustace AJ*, Toomey S*, Fay J, Sheehan KM, Carr A, Milewska M, Madden SF, Teiserskiene A, Kay EW, O’Donovan N, Gallagher WM, Grogan L, Breathnach O, Walshe J, Kelly C, Moulton B, Kennedy MJ, Gullo G, Hill AD, Power C, Duke D, Hambly N, Crown J, Hennessy BT.
  5. A preclinical evaluation of the PI3K inhibitor BAY80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2-targeted therapies trastuzumab and lapatinib. Breast Cancer Res Treat. 2015 Jan;149(2):373-83.
    Elster N, Cremona M, Morgan C, Toomey S, Carr A, O’Grady T, Hennessy B.T*, Eustace A.J*
Research Group Members

Arnau Cuy Sacs (PhD Student)

Studying Impact of PI3K/AKT pathway mutations on therapy response and resistance.  Funded by Health Research Board Emerging Investigator award.

Grace Colley (PhD Student)

Studying Impact of PI3K/AKT pathway mutations on therapy response and resistance.  Funded by Health Research Board Emerging Investigator award.

Dalal AlSultan (PhD Student)

Studying a pan-omic interrogation of trastuzumab response in HER2-positive Breast Cancer.  Funded by the Irish Research Council and the Cancer Clinical Research Trust through and Enterprise partnership award.

Laura Ivers (Research Assistant)

Translational coordinator between DCU and St Vincent’s University Hospital. Funded by the Cancer Clinical Research Trust.

Anita White (Research Assistant)

Studying impact of DNA damage response inhibitors in the treatment of cancer. Funded by the Cancer Clinical Research Trust.

Dr. Rabab Kaneez

Studying impact of PI3K/AKT pathway mutations on therapy response and resistance. Funded by Health Research Board Emerging Investigator award.

Principal Investigators

Dr. Denis Collins
denis.collins@dcu.ie
+353 (0) 1 700 5647

Dr. Denis Collins completed his undergrad in Biochemistry at University College Cork in 2001. His PhD thesis was carried out in DCU. It examined the ability of tyrosine kinase inhibitors to modulate the activity of drug efflux pumps involved in chemotherapy resistance in lung cancer. Dr. Collins held an IRCSET Enterprise Partnership Scheme Postdoctoral Fellowship from 2011-2013 examining the immune response to antibody therapies, spending six months working at Roche Diagnostics GmbH, Penzberg, Germany during this time. Dr. Collins went on to secure a Roche Postdoctoral Fellowship (RPF) from 2014-2017 that was carried out between the National Institute for Cellular Biotechnology (NICB), DCU and Roche Diagnostics GmbH in Germany. The RPF examined the impact of HER4 mutations on response to HER-family targeted therapies. Dr. Collins is currently the Caroline Foundation Senior Research Fellow and runs the Cancer Biotherapeutics group at the NICB, DCU. He is Co-PI on the Science Foundation Ireland Strategic Research Partnerships Programme Award ACORN and Chair of the Irish Association for Cancer Research Junior Council.

Biotherapeutics (biologics or biotech drugs) are at the forefront of modern cancer chemotherapy. Examples include the monoclonal antibodies trastuzumab, cetuximab and pertuzumab , the antibody drug conjugate T-DM1, the immune checkpoint inhibitors pembrolizumab, nivolumab and ipilimumab. These therapies are at the forefront of the effort to produce therapies with potent and specific anti-cancer activity.

The goal of the Cancer Biotherapeutics programme is to fully exploit the potential of these exciting new drugs by generating treatment option rationale for cancers with an unmet clinical need such as metastatic HER2+ breast cancer, triple negative breast cancer, lung cancer, oesophageal cancer and melanoma. Combinations of the biotherapeutics with existing small molecule inhibitors such as neratinib and lapatinib, and chemotherapeutic agents like docetaxel are investigated. Projects utilise cutting-edge laboratory techniques, unique cancer cell line-based resistance models and patient material obtained from the translational component of clinical trials carried out in Ireland.

Our objectives are to:

  1. Understand the interplay between biotherapeutics and the immune system in order to find new therapeutic targets or potential synergistic combinations with existing or novel chemotherapies.
  2. Determine the underlying mechanisms of innate and acquired resistance to biotherapeutics that limit the efficacy of these drugs in the clinic.
  3. Identify patients that will most benefit from biotherapeutics through the analysis of patient-derived material from translational studies.

Current projects are examining:

  1. The effects of breast and lung cancer-indicated tyrosine kinase inhibitors (TKI) on the immune response to trastuzumab, perjeta and T-DM1.
  2. Examining novel indications/combination strategies involving the TKI neratinib for the treatment of treatment refractory HER2+ breast cancer. SFI-funded ACORN – an industry/academia collaboration with Puma Biotechnology, Inc.
  3. Peripheral and tumour biomarkers of response to neratinib and other TKIs in HER2+ breast cancer – SFI-funded ACORN.
  4. HER2-targeted therapies for gastric and oesophageal cancers.
  5. The role of immune cell-expressed PD-1 (an immune checkpoint targeted by pembrolizumab and nivolumab in immune cell-mediated cytotoxicity in breast cancer patient samples.
  6. An assessment of the effects of chemotherapy on the plasma proteome of HER2+ breast cancer patients.

Recent Publications

  1. Eustace AJ, Madden SF, Fay J, Collins DM, Kay EW, Sheehan KM, Furney S, Moran B, Fagan A, Morris PG, Teiserskiene A, Hill AD, Grogan L, Walshe JM, Breathnach O, Power C, Duke D, Egan K, Gallagher WM, O’Donovan N, Crown J, Toomey S, Hennessy BT. The role of infiltrating lymphocytes in the neo-adjuvant treatment of women with HER2-positive breast cancer. Breast Cancer Res Treat 2021 May 13. PMID: 33983492 doi: 10.1007/s10549-021-06244-1.
  2. Conway C*, Collins DM*, McCann A, Dean K. Research Strategies for Low-Survival Cancers. Cancers 2021, 13(3), 528; PMID: 33573275 https://doi.org/10.3390/cancers13030528
  3. onlon NT, Kooijman JJ, van Gerwen SJC, Mulder WR, Zaman GDR, Diala I, Eli LD, Lalani AS, Crown J, Collins DM. Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors Br J Cancer (2021) Mar;124(7):1249-1259. PMID: 33473169 https://doi.org/10.1038/s41416-020-01257-x
  4. Collins DM, Madden SF, Gaynor N, AlSultan D, Le Gal M, Eustace AJ, Gately KA, Hughes C, Davies AM, Mahgoub T, Ballot J, Toomey S, O’Connor DP, Gallagher WM, Holmes FA, Espina V, Liotta L, Hennessy BT, O’Byrne KJ, Hasmann M, Bossenmaier B, O’Donovan N and Crown J. Effects of HER family-targeting tyrosine kinase inhibitors on antibody-dependent cell-mediated cytotoxicity in HER2-expressing breast cancer. Clinical Cancer Research February 1 2021 (27) (3) 807-8182020) DOI: 10.1158/1078-0432.CCR-20-2007 PMID: 33122343
  5. Gaynor N, O’Donovan N, Crown J and Collins DM. Immune checkpoint inhibitors: Key trials and an emerging role in breast cancer. Seminars in Cancer Biology (2020) Semin Cancer Biol 2020 Jul 2;S1044-579X(20)30152-8. PMID: 32623044
Research Group Members

Dr. Nicola Gaynor (Postdoctoral Fellow)

Immunotherapies and biomarkers of response, funded by The Caroline Foundation

Dr. Neil Conlon (Postdoctoral Fellow)

Novel anti-cancer combinations and drug resistance funded by the Irish Research Council and the Cancer Clinical Research Trust

Dr. Mohammed Al Azzawi (MD student)

pan-HER TKI GI cancer treatments, funded by the Cancer Clinical Research Trust

Dr. Amira Mahdi (Postdoctoral Fellow)

Novel combinations in HER2+ breast cancer, funded by SFI ACORN

Dr. Debbie O’Reilly (Postdoctoral fellow)

Biomarkers of response to TKIs in HER2+ breast cancer, funded by SFI ACORN

Myra Castel (PhD student)

Novel TKI combinations in non-breast cancers, funded by SFI ACORN

Marta Valenti (PhD Student)

HER4 as a biomarker of response to TKIs, funded by SFI ACORN

Niall Ashfield (PhD student)

Small molecule TKIs and antibody-drug conjugates for the treatment of HER2+ cancer, funded by the Irish Research Council and the Cancer Clinical Research Trust