|Development of personalised medicine approaches for the clinical application of IAP antagonists in metastatic and high risk early stage colorectal cancer|
|Colorectal cancer (CRC) has the second highest mortality rate of any cancer in Europe. Globally, there are 1.2 million cases diagnosed each year. For current therapies, the weekly cost per patient can reach €5,000, but benefits to patients are limited. 5-year survival rates have increased only moderately in the past 25 years, indicating a need for novel therapies that target cancer resistance. However, devising new therapies but not knowing which patients will ultimately benefit from these is unsustainably costly. Based on novel diagnostic tools and a substantial body of biomedical, pre-clinical and clinical data generated by the applicant group, this proposal explores the hypothesis that subgroup(s) of colorectal tumours become addicted to inhibitor-of-apoptosis (IAP) proteins, thereby suppressing both apoptosis and immune signalling, and that such subgroup(s) can be effectively treated by novel IAP-targeted therapeutic drugs. We will identify sub-groups of patients not benefiting from current chemotherapy, examine which subgroup(s) of tumours are re-sensitized by IAP antagonist therapy, and will deliver a new generation of systems-based patient stratification tools for future integration into ‘smart’ clinical trials. Our proposal will deliver new solutions for the personalised therapy of CRC, and addresses these in a systematic, step-wise manner.
Project ends 2017 Funded by SFI
From population to patient: Leveraging systems medicine to personalise breast cancer treatment: Systems modelling of apoptosis signalling in breast cancer
ICS BREAST-PREDICT Cancer Research Centre aims to develop systems-level clinical, pathophysiological and pharmacoepidemiological data-driven approach that will facilitate evidence-based predictive breast cancer medicine. Founded upon the rationalisation of national data and bioresources, together with advanced mining of publically available datasets, BREAST-PREDICT Centre will utilise systems medicine-based approaches to (a) model effects of pharmacoepidemiological, comorbidity and lifestyle factors on breast cancer outcome; (b) examine adaptive responses of breast tumours to targeted therapy; (c) identify rational combinatorial therapeutic regimes; (d) provide mechanistic anchoring of key breast cancer-driving pathways; and, (e) facilitate validation of signature-based diagnostics that can predict outcome and response to therapeutic intervention. To achieve this, a comprehensive analysis of breast tumours and associated bioresources from retrospective cohorts, ongoing prospective trials and novel prospective trials will be performed utilising next generation sequencing approaches and antibody-based proteomics, while functional genomic approaches will be employed to identify novel therapeutic targets and rational combinations of existing drugs. Findings will be mechanistically evaluated in vitro and in vivo using animal models and non-invasive imaging techniques. In summary, the BREAST-PREDICT Centre will facilitate the rationalisation of drug utilisation prior to and during breast cancer therapy and inform the next generation of hypothesis-driven research and clinical trials. funded by the Irish Cancer Society. Ends: 30/09/2018
|A systems-based patient stratification tool of Bcl-2 family protein interactions to evaluate acute treatment responses in rectal cancer patients
Cancers of the rectum (the lower part of the large intestine where the body stores stool) are a common cause of cancer-related death in Ireland and cause a significant burden to the quality of life of affected patients. Surgery is the mainstay for the treatment of rectal cancer, but surgeons often prefer to ‘downstage’ or ‘shrink’ the tumour prior to surgery in order to achieve a better surgical outcome and to reduce surgical complications or the necessity of a stoma. This ‘downstaging’ of the tumour is achieved through aggressive radio- and chemotherapy over a period of 2-3 months, however many patients will not respond to this treatment because their cancer cells are resistant to such therapy. Hence for a majority of patients the radiochemotherapy may not only be unnecessary, but may even delay surgery and increase the risk of further tumour progression. In a previous, successful study in colon and rectal cancer patients 1, we developed a new test that is capable of telling the surgical and medical teams whether a patient will respond or not to radiochemotherapy by analysing a set of proteins from a small biopsy of the tumour that is routinely taken during medical examination. Rather than looking at individual proteins or genes, this diagnostic test takes into account the complex regulation of tumour cell death in response to radiochemotherapy. Here we will validate this new diagnostic tool in a larger cohort of rectal cancer patients, and will further improve it by investigating whether the inclusion of important genetic and other patient data increases its predictive power. Finally, we will investigate whether this new diagnostic tool can also be used to identify those patients who may benefit from novel therapeutics that target cell death defects and that are currently in the clinical testing phase. Funded by the HRB; Ends: 30-9-17
BCL-2 family proteins and cellular bioenergetics in the control of cell survival: Towards novel predictive and prognostic markers for disease progression and therapy responses in colorectal cancer patients
Colorectal cancer (CRC) is frequently diagnosed in its later stages where there is local, lymphatic or metastatic spreading, indicating a need for adjuvant or palliative chemotherapy. However, response rates to 5-FU-based chemotherapy remain low.
BCL-2 family proteins and cellular bioenergetics are master regulators of cancer cell survival, and key factors in the development of chemotherapy resistance. Based on experimental and clinical proof-of-concept work, the current programme seeks to identify,
test, and validate novel predictive and prognostic tools centred on an integrated, systems analysis of apoptosis signalling, cellular bioenergetics, and their dependence on genetic/epigenetic signatures in CRC. We will deliver novel signatures and computational
models of tumour responsiveness to genotoxic treatment, and will translate existing and novel computational models of BCL-2 protein interactions and cellular bioenergetics into the clinical setting by evaluating therapy responses in stage 2 and 3 CRC
patients. As a final objective we will identify novel molecular determinants of survival- and death- promoting activities of the energy sensor, AMP-activated- protein-kinase to identify novel biomarkers that may operate cell-autonomously or in paracrine. In
conclusion, the programme will deliver a new generation of diagnostics and systems-based stratification tools designed to facilitate the clinical management of CRC patients.
Funded By SFI ( Investiagator programme award)
The impact of hypoxia on inflammation and tumorigenesis in Ulcerative Colitis
Hypoxia, Inflammatory Bowel Disease, Inflammation.
Ulcerative colitis (UC) is a debilitating intestinal inflammatory disorder affecting approximately 1:200 people, the prevalence of which is disproportionately high in Europe.
– Our central hypothesis is that microenvironmental hypoxia, through HIF activation, is a key determinant of inflammation and subsequent tumour development in UC patients, and that the critical link between clinical phenotype and molecular pathogenetic mechanisms can be made by computational modelling.
-Based on this hypothesis we will pursue an approach that is led by clinical features and then uses an array of experimental and theoretical models to elucidate molecular mechanisms of disease progression that will allow us (i) to assess the individual patients’ risk of UC to cancer
progression, and (ii) to design new therapies based on mechanistic systems level understanding of the pathology.
-The overall impact of this study will be to provide a demonstrator project for how systems medicine approaches can advance the personalised diagnosis and treatment of UC based on modelling the mucosal hypoxic response and predicting how this impacts upon disease progression. Funded by ERACoSysMed. Ends 30-4-19
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