Belfield, Ireland
Belfield, Ireland

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Grant
Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-2009-IAPP | Award Amount: 1.76M | Year: 2010

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 is 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 is 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 is 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 will be engaged to comprehensively describe a new AngioTox Safety Panel of toxicologic markers. We will develop automated image analysis algorithms to enable quantification of morphological markers of angiogenesis inhibitor toxicity, and will undertake molecular profiling and ex-vivo studies to gain insight into mechanistic pathways. Specialized secondments proposed within AngioTox will facilitate several opportunities for high-end training of researchers across both industry and academia. Findings from the AngioTox programme may be 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.


Grant
Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2014-ETN | Award Amount: 3.61M | Year: 2014

Novel treatment options and associated personalised, patient-tailored therapies need to be explored and developed for highly heterogeneous and chemotherapy resistant cancers, such as malignant melanoma. This can only be achieved by industry-academia collaborations in newly emerging, innovative research disciplines such as translational cancer systems biology and systems medicine. These disciplines and the associated European training needs provide the foundation for the MEL-PLEX ETN. MEL-PLEX aims to understand the network-level and multi-scale regulation of disease-relevant signalling in melanoma through a combination of quantitative biomedical and computational research approaches that go significantly beyond the current state-of-the-art. Coordinated by the RCSI Centre for Systems Medicine, MEL-PLEX will train 15 early stage researchers through a highly interdisciplinary and intersectoral research training programme. MEL-PLEX comprises 11 beneficiaries and 7 partner organisations from 11 countries, including European and international leaders in personalised melanoma therapy, melanoma systems biology and cancer systems medicine. MEL-PLEX aims to (i) achieve an unmatched depth of molecular and mechanistic disease understanding, (ii) will exploit this knowledge to develop and validate predictive models for disease progression, prognosis and responsiveness to current and novel (co-)treatment options, and (iii) will provide superior and clinically relevant tools and biomarker signatures for personalising and optimising melanoma treatment. The MEL-PLEX ETN addresses current needs in academia and the private sector for researchers that have been trained in an environment that spans across biology, medicine and mathematics, that can navigate confidently between clinical, academic and private sector research environments, and that have developed an innovative and creative mindset to progress research findings towards applications.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.1.2-1 | Award Amount: 3.90M | Year: 2012

With the arrival of new colorectal cancer (CRC) therapeutics targeting specific cell signalling pathways, such as anti-EGFR therapy, personalised cancer treatment is at the door step of clinical practise. This progress in drug development contrasts strikingly with current clinical practice, where decision making depends largely on clinical factors such as tumour staging and age of patient, with the success of such treatments being largely unpredictable. 5-FU-based chemotherapy represents the main stay of CRC therapy. DNA damaging agents such as 5-FU and anti-EGFR therapy seek to induce tumour regression through induction of apoptosis or sensitization to apoptosis. Dysfunctional apoptosis is well recognized as a key contributing factor in chemotherapy resistance. The aim of the APODECIDE consortium is to develop systems medicine tools that predict treatment responses in CRC patients to 5-FU-based chemotherapy and anti-EGFR therapy, based on a systems analysis of apoptosis and EGFR signalling pathways. Based on previous clinical proof-of-concept studies that demonstrated the unique potential of such approaches in predicting tumour resistance, the APO-DECIDE consortium aims to deliver new clinical decision making tools that enable personalised medicine approaches and smart clinical trials design in the future. The SMEs will benefit from the project through the development of systems-based combinatorial biomarkers adapted to formalin fixed paraffin-embedded material, the routine material used in clinical histopathology, hence providing a unique opportunity for marketing and exploitation. SMEs and their academic partners will also develop computational whole body models reflecting drug pharmacodynamics and pharmacokinetics in patient cohorts, providing a unique market niche in the field clinical oncology.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2011.1.1-2 | Award Amount: 7.99M | Year: 2012

In recent years the treatment paradigm for metastatic colorectal cancer (mCRC) has evolved in complexity to include newly developed targeted therapeutics. 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 will be validated for markers of Intrinsic Resistance to therapy. Parallel optimization of companion in vitro diagnostic tests (IVDs) through exploitation of proven SME development and validation strategies will ensure a cross-sectoral benefit to the cancer patient, prescribing physician and more broadly, across European and global public health networks. Crucially, leading SME partners will expand business portfolios into a well-defined market, progress novel intellectual property and access several in-licensing opportunities. ANGIOPREDICT uniquely unites world-class molecular diagnostic biomarker discovery SMEs with leading clinical and academic entities to identify a new generation of individualized methods for predicting response to combination bvz therapy.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-IAPP-2008 | Award Amount: 1.74M | Year: 2009

Transformed melanocytes use several strategies to enable their progression to advanced melanoma and metastasis, including genetic and epigenetic alterations, along with disruptions to gene and protein expression. This consortium aims to identify novel biomarkers for predicting the progression and prognosis of melanoma. To achieve this, a concerted collaborative effort is proposed here between key academic and industrial partners, centred on intersectorial training of experienced researchers. Our first goal is to identify novel methylated genes via several complementary screening methods, followed by validation extensive melanoma cohorts available to the consortium. We will use the following strategies to identify methylated genes: (1) an array-based technique called MeDIP-ON-CHIP, (2) a high-throughput bisulphite-based technique developed by Illumina (to simultaneously analyse up to 800 genes over 96 samples) and (3) in silico analysis of DNA microarray data. To validate these methylation targets, we will use both qualitative and quantitative methylation-specific PCR (MSP) and determine if these methylation events correlate with melanoma progression, i.e. from benign and atypical nevi to primary and metastatic tumours. Our second goal is to validate genes that associate with melanoma progression and prognosis. For this aspect of the project, we will concentrate on the application of tissue microarray technology and associated image analysis approaches to validate molecular determinants of melanoma progression. Prioritised targets will then be functionally validated by a unique in vitro assay that models extravasation, or exit of cancer cells out of the blood stream, a key step in the metastatic process. Overall, these studies will give clues to melanoma progression, and may identify important targets for melanoma treatment. In addition, this industry-academic partnership will provide a valuable cross-disciplinary training ground for emerging researchers.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-2013-IAPP | Award Amount: 1.81M | Year: 2013

Worldwide figures show that there were 160,000 incidences of melanoma in 2002, whilst 39,000 died from the disease. These upward trends are worrying, as malignant melanoma is one of the most difficult cancers to treat, due to its ability to spread quickly and its resistance to standard chemotherapeutic agents. In order to counteract this trend, targeted therapies that inhibit melanoma metastasis are required. The aim of SYS-MEL is to identify and validate prognostic and predictive biomarkers for melanoma, and to model the predictive value of these biomarkers in determining the efficacy of melanoma therapies. The central objective is to bring together four European academic institutes and two SMEs to develop 3 prognostic/predictive biomarker assays for melanoma. 3 core areas of interest are epigenetics, signalling pathways in melanoma and systems biological approaches for predicting chemotherapy responses. SYS-MEL will have three main elements: 1) Epigenomic and protein expression analysis of melanoma tissue, to validate an epigenomic signature initially identified in the FP7-funded programme Target-Melanoma; 2) In silico modelling and prediction of patient responses to decarbazine DTIC using both in vitro analysis of apoptotic pathways and a novel systems biology approach, incorporating mathematical systems modelling, quantitative biochemistry and cell biology; 3) Investigating the components of the P-Rex1 pathway that are involved in driving the migration of melanoblast cells, and thus the progression of metastasis, incorporating a computational system tailored to model complex signalling pathways. This approach will enable us to identify prognostic and predictive biomarkers for melanoma, and to develop a powerful computational modeling approach to predict disease progression and patient responses to treatment.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-2011-IAPP | Award Amount: 1.95M | Year: 2011

Histopathology has traditionally been a low-throughput, labour-intensive technique. Conventional manual annotation of tissue slides requires a pathologist to examine the tissue and cellular components to grade the level of disease progression. However, digital pathology and automated digital image analysis solutions can provide a more rapid solution. In recent years, there has been a rapid uptake of digital pathology in both the academic and industrial sectors, each creating large image libraries with related manual and automated annotations, all stored on local systems. There is now a requirement to streamline this process and to provide a comprehensive set of tools for data integration and mining of this valuable, but often not fully exploited, information. There is also a need for inter-lab standardisation and the development of high-performance computing approaches to enable integration of multiple libraries and knowledge discovery. The FAST-PATH project will address these key issues to maximise the capabilities of the digital pathology workflow. Specifically, FAST-PATH will develop a set of tools, available through a web-based interface, to address the standardisation, integration and knowledge discovery of high-throughput digital pathology libraries and related manual annotations. We will focus on integration of oncology-based data generated from the academic and industrial partners involved, with a particular emphasis on prostate cancer. This inter-sectoral study will also involve validation of novel prognostic biomarkers via automated analysis of immunohistochemical images. Importantly, FAST-PATH will bring together 4 major European academic institutes and 2 SME partners with the central aim of streamlining digital pathology via the development of data standardisation, integration and discovery tools.


O'Hurley G.,University College Dublin | O'Hurley G.,Uppsala University | O'Hurley G.,OncoMark Ltd | Sjostedt E.,Uppsala University | And 7 more authors.
Molecular Oncology | Year: 2014

The use of immunohistochemistry (IHC) in clinical cohorts is of paramount importance in determining the utility of a biomarker in clinical practice. A major bottleneck in translating a biomarker from bench-to-bedside is the lack of well characterized, specific antibodies suitable for IHC. Despite the widespread use of IHC as a biomarker validation tool, no universally accepted standardization guidelines have been developed to determine the applicability of particular antibodies for IHC prior to its use. In this review, we discuss the technical challenges faced by the use of immunohistochemical biomarkers and rigorously explore classical and emerging antibody validation technologies. Based on our review of these technologies, we provide strict criteria for the pragmatic validation of antibodies for use in immunohistochemical assays. © 2014 Federation of European Biochemical Societies.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.4.1-8 | Award Amount: 7.79M | Year: 2011

Cancer genotyping has identified a number of correlations between mutations in specific genes and responses to targeted anti-cancer drugs, with many mutations occurring in kinases or downstream signaling components. While there are several ongoing large-scale genome re-sequencing studies for the major cancer types, there is no systematic effort to investigate kinase mutations in distinct biological subtypes of these cancers. Here, we will explore the rate of activation of all kinases (the kinome) in two poor-prognosis subtypes of breast cancer for which there are currently no targeted therapies available, namely triple negative (TN) breast tumors lacking the estrogen-, progesterone- and HER2 receptors, constituting 15% of breast cancers, and invasive lobular carcinomas (ILC) of the breast, which represent 10% of breast tumors. Thus, we lack effective targeted therapies for one quarter of all breast cancer patients. In this project, we will identify and validate novel kinase targets for therapy for these TN and ILC subtypes. Kinase targets will be identified via a 4-pronged approach: i) direct re-sequencing of the kinome of 150 TN and 150 ILC tumors, ii) determination of abundance and activation status of kinases in these tumors by reverse phase protein array and tissue microarray technologies, iii) determination of copy number variation by SNP arrays, and iv) mRNA quantitation of the kinome using DNA microarrays. Potential kinase targets for therapy will be validated in preclinical models using RNA interference. Finally, we will perform a phase I/II clinical trial to test the efficacy of a selective PI3K inhibitor in breast cancer. The project will deliver proof-of-concept for novel therapeutic interventions, together with matched molecular diagnostic approaches for patient stratification, for up to 25% of breast cancer patients.

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