Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy

Hdl Handle:
http://hdl.handle.net/10147/229137
Title:
Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy
Authors:
Hector, S.; Rehm, M.; Schmid, J.; Kehoe, J.; McCawley, N.; Dicker, P.; Murray, F.; McNamara, D.; Kay, E. W.; Concannon, C. G.; Huber, H. J.; Prehn, J. H. M.
Citation:
Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy 2011, 61 (5):725 Gut
Journal:
Gut
Issue Date:
15-Jun-2012
URI:
http://hdl.handle.net/10147/229137
DOI:
10.1136/gutjnl-2011-300433
Additional Links:
http://gut.bmj.com/cgi/doi/10.1136/gutjnl-2011-300433
Abstract:
Objective Key to the clinical management of colorectal cancer is identifying tools which aid in assessing patient prognosis and determining more effective and personalised treatment strategies. We evaluated whether an experimental systems biology strategy which analyses the susceptibility of cancer cells to undergo caspase activation can be exploited to predict patient responses to 5-fluorouracil-based chemotherapy and to case-specifically identify potential alternative targeted treatments to reactivate apoptosis. Design We quantified five essential apoptosis-regulating proteins (Pro-Caspases 3 and 9, APAF-1, SMAC and XIAP) in samples of Stage II (n=13) and III (n=17) tumour and normal colonic (n=8) tissue using absolute quantitative immunoblotting and employed systems simulations of apoptosis signalling to predict the susceptibility of tumour cells to execute apoptosis. Additional systems analyses assessed the efficacy of novel apoptosis-inducing therapeutics such as XIAP antagonists, proteasome inhibitors and Pro-Caspase-3-activating compounds in restoring apoptosis execution in apoptosis-incompetent tumours. Results Comparisons of caspase activity profiles demonstrated that the likelihood of colorectal tumours to undergo apoptosis decreases with advancing disease stage. Systems-level analysis correctly predicted positive or negative outcome in 85% (p=0.004) of colorectal cancer patients receiving 5-fluorouracil based chemotherapy and significantly outperformed common uni- and multi-variate statistical approaches. Modelling of individual patient responses to novel apoptosis-inducing therapeutics revealed markedly different inter-individual responses. Conclusions Our study represents the first proof-of-concept example demonstrating the significant clinical potential of systems biology-based approaches for predicting patient outcome and responsiveness to novel targeted treatment paradigms.
Item Type:
Article In Press
Language:
en
ISSN:
0017-5749

Full metadata record

DC FieldValue Language
dc.contributor.authorHector, S.en_GB
dc.contributor.authorRehm, M.en_GB
dc.contributor.authorSchmid, J.en_GB
dc.contributor.authorKehoe, J.en_GB
dc.contributor.authorMcCawley, N.en_GB
dc.contributor.authorDicker, P.en_GB
dc.contributor.authorMurray, F.en_GB
dc.contributor.authorMcNamara, D.en_GB
dc.contributor.authorKay, E. W.en_GB
dc.contributor.authorConcannon, C. G.en_GB
dc.contributor.authorHuber, H. J.en_GB
dc.contributor.authorPrehn, J. H. M.en_GB
dc.date.accessioned2012-06-15T13:36:57Z-
dc.date.available2012-06-15T13:36:57Z-
dc.date.issued2012-06-15-
dc.identifier.citationClinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy 2011, 61 (5):725 Guten_GB
dc.identifier.issn0017-5749-
dc.identifier.doi10.1136/gutjnl-2011-300433-
dc.identifier.urihttp://hdl.handle.net/10147/229137-
dc.description.abstractObjective Key to the clinical management of colorectal cancer is identifying tools which aid in assessing patient prognosis and determining more effective and personalised treatment strategies. We evaluated whether an experimental systems biology strategy which analyses the susceptibility of cancer cells to undergo caspase activation can be exploited to predict patient responses to 5-fluorouracil-based chemotherapy and to case-specifically identify potential alternative targeted treatments to reactivate apoptosis. Design We quantified five essential apoptosis-regulating proteins (Pro-Caspases 3 and 9, APAF-1, SMAC and XIAP) in samples of Stage II (n=13) and III (n=17) tumour and normal colonic (n=8) tissue using absolute quantitative immunoblotting and employed systems simulations of apoptosis signalling to predict the susceptibility of tumour cells to execute apoptosis. Additional systems analyses assessed the efficacy of novel apoptosis-inducing therapeutics such as XIAP antagonists, proteasome inhibitors and Pro-Caspase-3-activating compounds in restoring apoptosis execution in apoptosis-incompetent tumours. Results Comparisons of caspase activity profiles demonstrated that the likelihood of colorectal tumours to undergo apoptosis decreases with advancing disease stage. Systems-level analysis correctly predicted positive or negative outcome in 85% (p=0.004) of colorectal cancer patients receiving 5-fluorouracil based chemotherapy and significantly outperformed common uni- and multi-variate statistical approaches. Modelling of individual patient responses to novel apoptosis-inducing therapeutics revealed markedly different inter-individual responses. Conclusions Our study represents the first proof-of-concept example demonstrating the significant clinical potential of systems biology-based approaches for predicting patient outcome and responsiveness to novel targeted treatment paradigms.en_GB
dc.language.isoenen
dc.relation.urlhttp://gut.bmj.com/cgi/doi/10.1136/gutjnl-2011-300433en_GB
dc.rightsArchived with thanks to Guten_GB
dc.titleClinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapyen_GB
dc.typeArticle In Pressen
dc.identifier.journalGuten_GB
dc.description.provinceLeinsteren
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