FUNDING

The National Preclinical Imaging Centre (NPIC), which is the first of its kind in Ireland, has been established and co-funded by RCSI University of Medicine and Health Sciences, University College Dublin (UCD), and CÚRAM, the SFI Research Centre for Medical Devices, based at National University of Ireland Galway (NUI Galway).

The Centre’s imaging infrastructure supports the development of new therapeutics and diagnostics in human disease areas including cancer, neurology, dementia, psychiatry, cardiology, medical devices, diabetes, tissue engineering, nanomedicine and inflammatory disease. 

The Centre provides a national pre-clinical imaging resource open to all academic, industry and not-for-profit researchers, and has locations in Dublin (RCSI, UCD) and Galway (NUI Galway). NPIC establishes a national pre-clinical magnetic resonance (MR) facility, a national high-field preclinical MR / chemical imaging platform and incorporates a high-resolution micro-computed tomography (CT) and Optical Imaging laboratory.

Funder: SFI

www.NPIC.ie

ResearchGate page

Colorectal cancer (CRC) is the third most common cancer in Europe. It is estimated that 50-55% harbour RAS mutations. Current treatment for RAS mutant(mt) metastatic(m) CRC is based on 5-fluoruracil based chemotherapy +/- bevacizumab. There are limited treatment options once cancers become resistant. Targeted treatment of microsatellite stable (MSS) RAS mt disease is difficult and has not evolved significantly in recent years. COLOSSUS looks to deliver novel concepts for disease-mechanism based patient stratification in MSS RAS mt mCRC to address the need for stratified or personalised therapies. The consortium aims to integrate multidimensional and longitudinal omics data to identify new MSS RAS mt specific subtypes. Systems biomedicine, network analysis and computational modelling are utilised to identify new actionable pathways, biomarkers and targets across subtypes. These targets are then interrogated in pre-clinical patient derived xenograft studies. Newly described MSS RAS mt classifiers are then validated within the COLOSSUS trial. These results are then used by our SME partners to develop clinically relevant and commercially viable assays for outcome prediction and stratification of MSS RAS mt patients based on novel classifiers. This work also includes patient associations through which perform public and and patient involvment (PPI) events are hosted.

Funder: Horizon 2020 

www.colossusproject.eu

Counteracting high attrition rates in oncology drug development and providing optimal therapeutic management of cancer patients require preclinical models that properly recapitulate the complexity and diversity of human tumours. Patient-derived tumour xenografts (PDXs), established by transplanting tumour fragments into immunodeficient mice, are being widely embraced by the scientific community as preclinical tools for target and biomarker discovery. The overall goal of EDIReX is to establish a cutting-edge European infrastructure offering Trans-national Access (TA) of PDX resources to academic and industrial cancer researchers, including the distribution of cryopreserved samples to third parties, the structured biobanking of user-developed models, and the performance of efficacy studies.

Funder: Horizon 2020 

www.europdx.eU

Colorectal cancer (CRC) is the third most common cancer in Europe with an estimated 420,000 new cases diagnosed and 230,000 related deaths anticipated in 2018. CRC is the 2nd most common and 2nd most fatal cancer in Ireland. Currently standard chemotherapy (FOLFOX) and bevacizumab [(BVZ); avastin] a drug which inhibits tumour blood vessel formation are standard of care treatments for CRC patients. However, only a subpopulation of patients benefit from treatment and for the majority, their tumors regrow and spread to distant organs like the liver and lungs. Furthermore, avastin is a costly drug and has some serious side effects. Recently we have discovered that chromosomal instability (where whole human chromosomes or parts of chromosomes are duplicated or deleted) may predict which patients will receive most benefit to avastin. By predicting the patients that would not benefit from avastin, individuals could be spared the side effects of this particular drug therapy, and are more likely to receive optimal treatment with a minimum of delay, while reducing cost of care. Based on these findings, we now wish to develop a laboratory test, which can be used in patients to detect these chromosomal rearrangements in DNA that is found freely in blood. This test will be based on a simple blood test making it easy to screen patients and predict whom will likely respond to avastin treatment    

Funder: HRB

Colorectal cancer is often treated with chemotherapy and Avastin. However, Avastin only benefits a sub-group of patients. Recently, we discovered that chromosomal instability (chromosomes duplicated or deleted) may represent a “biomarker’ to predict which patients might respond. To understand how our biomarker works, we must now unravel the underpinning biological mechanisms. We will do this by analysing genetic data from patients and utilising preclinical models, medical imaging and tumour protein analyses. Overall, this will help us take our new biomarker into the clinic, with an overall goal to improve colorectal cancer patient care and outcomes

Funder: SFI

Lead PI: Prof Mark Cunningham - TCD

Seizures are a frequent symptom for patients with brain tumours and are poorly controlled. These seizures are due to an increased level of a chemical messenger, or neurotransmitter, around the tumour. Neurotransmitters such as glutamate allow brain cells to talk to one another. Glutamate does this by exciting brain cells. Excessive glutamate overexcites brain cells around the tumour causing seizures. We will explore the potential to use a gene therapy approach to deliver a protein to the brain that in the presence of excessive glutamate will silence abnormal brain cells to stop seizures.

Funder: SFI

We would like to express our gratitude to all the funding agencies who have supported our work, including Science foundation Ireland, the Health Research Board, the Irish Cancer Society, Enterprise Ireland, Beaumont Hospital Foundation and the EU

Completed Projects

Glioblastoma (GBM) is the most frequent, aggressive and lethal brain tumour. It has a universally fatal prognosis with 85% of patients dying within two years. New treatment options and precision medicine therapies are required. This must be achieved by multi-sectoral industry-academia collaborations in newly emerging, innovative research disciplines. The research objective of GLIOTRAIN is to identify novel therapeutic strategies for GBM, implementing NGS, systems medicine and integrative multi-omics to unravel disease resistance mechanisms. Research activities incorporate applied systems medicine, integrative multi-omics and translational cancer biology implementing clinically relevant models. The consortium brings together leading European and international academics, clinicians, private sector and not-for-profit partners across GBM fields of tumour biology, multiomics, drug development, clinical research, bioinformatics, computational modelling and systems biology. Thus, GLIOTRAIN addresses currently unmet translational research and clinical needs in the GBM field by interrogating innovative therapeutic strategies and improving the mechanistic understanding of disease resistance. The ETN trains 15 innovative, creative and entrepreneurial ESRs. The GLIOTRAIN ETN addresses current needs for researchers trained in an environment that spans translational research, medicine and computational biology, and that can navigate confidently between clinical, academic and private sector environments to progress applied research findings towards improved patient outcomes.

Funder: Horizon 2020

www.gliotrain.eu/

The ColoForetell project had identified as a primary goal, the discovery & verification of predictive pharmaco-omic & imaging methods for regorafenib in mCRC patients who have disease progression despite all currently available standard therapies. This project utilized a state of the art mCRC Patient Derived Xenograft (PDX) platform to enable the systematic and integrated interrogation of predictive ‘omic andimaging markers of intrinsic resistance to regorafenib. Emergent pre-clinical biomarker data were cross-validated with biomarker candidates arising from genomic biomarker discovery studies implementing ‘CORRECT’ Trial primary tumour biopsy samples. Data was integrated and analysed using conventional statistics and where appropriate, systems modelling approaches. Our ultimate goal was the emergence of integrated prognostic tools for the early prediction of patient outcome following REG treatment. The Coloforetell initiative sought to exploit a multi-dimensional modular strategy towards the focused identification of efficacy biomarkers, to predict patient response to REG therapy in mCRC where response rate heterogeneity had been confirmed. This integrative approach expanded on the integrative paradigm employed in the multi-millionEuro EU funded ‘ANGIOPREDICT’ initiative to employ mCRC PDX modelling and molecular imaging as state of the art tools in pre-clinical biomarker identification. 

Funder: Science Foundation Ireland

In 2004 bevacizumab (bvz) [Avastin] became the first anti-angiogenic drug to be licensed in malignant disease, based on the results of a randomised trial in advanced metastatic colorectal cancer. Nevertheless, over the past six year period emerging data now indicates that bvz fails to produce an enduring clinical response in a high proportion of patients. Delivery of the drug as part of a combination treatment regimen in mCRC elicits transitory improvements in the form of tumour stasis or shrinkage. Inevitably however, the tumours begin to re-grow and the disease progresses. It is now universally agreed that the future use of bvz in mCRC (and other cancers) is likely to be greatly influenced by the availability of predictive biomarkers to allow selection of patients who will attain the greatest benefit. The ANGIOPREDICT paradigm relies on a modular platform for the integrated discovery and validation of predictive pharmacogenomic biomarkers for combination bvz therapy in mCRC. Through initiation of a multi-centre clinical trial, early discovery findings were validated for markers of Intrinsic Resistance to therapy.

Funder: EU Framework Programme 7

Outputs:

Sturrock M, Miller IS, Kang G, Hannis Arba’ie N, O’Farrell AC, Barat A, Marston G, Coletta PL, Byrne AT, Prehn JH. Anti-angiogenic drug scheduling optimisation with application to colorectal cancer. Scientific Reports 8(1) 01 Dec 2018

Smeets D, Miller IS, O’Connor DP, Das S, Moran B, Boeckx B, Gaiser T, Betge J, Barat A, Klinger R, et al. Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy. Nature Communications 9(1) 01 Dec 2018

Van Dijk E, Biesma HD, Cordes M, Smeets D, Neerincx M, Das S, Eijk PP, Murphy V, Barat A, Bacon O, et al. Loss of chromosome 18q11.2-q12.1 is predictive for survival in patients with metastatic colorectal cancer treated with bevacizumab. Journal of Clinical Oncology 36(20):2052-2060 10 Jul 2018

Moran B, Das S, Smeets D, Peutman G, Klinger R, Fender B, Connor K, Ebert M, Gaiser T, Prehn JHM, et al. Assessment of concordance between fresh-frozen and formalin-fixed paraffin embedded tumor DNA methylation using a targeted sequencing approach. Oncotarget 8(29):48126-48137 01 Jan 2017

Inhibition of angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a well established therapeutic strategy against cancer. Inhibitors of angiogenesis have been developed to block tumour growth and metastasis, and a number of these inhibitors are now clinically approved. However, contrary to initial expectations, angiogenesis inhibitors can cause a range of toxicities in patients. AngioTox was a cross-sectoral collaboration in the field of biomedicine, responding to a pressing need to understand mechanisms of toxicity associated with angiogenesis inhibitor treatment. AngioTox was comprised of academic groups, SMEs, a global pharmaceutical leader in angiogenesis inhibitor development, and a large company concerned with monitoring drug modulation of cellular pathways. The goal of this consortium was to facilitate comprehensive histopathologic and mechanistic assessment of angiogenesis inhibitor related toxicities following treatment with the two main class of angiogenesis inhibitor; monoclonal antibodies and tyrosine kinase inhibitors. A combined in vivo modelling and digital histopathology approach was engaged to comprehensively describe a new AngioTox Safety Panel of toxicologic markers. We developed automated image analysis algorithms to enable quantification of morphological markers of angiogenesis inhibitor toxicity, and undertook molecular profiling and ex-vivo studies to gain insight into mechanistic pathways. Specialised secondments proposed within AngioTox facilitated several opportunities for high-end training of researchers across both industry and academia. Findings from the AngioTox programme were directly utilised by academic, clinical and industry-based investigators to facilitate improved screening of angiogenesis inhibitor toxicologic parameters, inform clinical drug dosing regimens, facilitate the development of more specific and potent angiogenesis inhibitors, and significantly improve patient care.

Funder: EU Framework Programme 7

Outputs:

Gullo G, J. Eustace A, Canonici A, M. Collins D, Kennedy MJ, Grogan L, Breathhnach O, McCaffrey J, Keane M, Martin MJ, Gupta R, Leonard G, O’Connor M, Calvert PM, Donnellan P, Walshe J, McDermott E, Scott K, Hernando A, Parker I, W. Murray D, C. O’Farrell A, Maratha A, Dicker P, Rafferty M, Murphy V, O’Donovan N, M. Gallagher W, Ky B, Tryfonopoulos D, Moulton B, T. Byrne A, Crown J.  Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER-2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08–10 trial. Therapeutic Advances in Medical Oncology. 11. Published 1 Jul 2019

O'Farrell AC, Miller IS, Evans R, Alamanou M, Cary M, Mallya Udupi G, Lafferty A, Monsefi N, Cremona M, Prehn JHM, et al. Implementing Reverse Phase Protein Array Profiling as a Sensitive Method for the Early Pre-Clinical Detection of Off-Target Toxicities Associated with Sunitinib Malate. Proteomics - Clinical Applications 01 Jan 2019

O'Farrell AC, Evans R, Silvola JMU, Miller IS, Conroy E, Hector S, Cary M, Murray DW, Jarzabek MA, Maratha A, et al. A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate. PLoS ONE 12(1) 01 Jan 2017

NPIC

COLOSSUS

Europdx

HRB Liquid Biopsy

SFi chromosomal instability

SFI BTRE Gene Therapy

Gliotrain

Coloforetell

Angiopredict

Angiotox