Funding

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

Output:

Byrne AT, Alférez DG, Amant F, Annibali D, Arribas J, Biankin AV, Bruna A, Budinská E, Caldas C, Chang DK, et al. Interrogating open issues in cancer medicine with patient-derived xenografts. Nature reviews. Cancer 17(10):632 15 Sep 2017 (Journal article)

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

Europdx

Gliotrain

Coloforetell

Angiopredict

Angiotox