Type

Journal Article

Authors

Jochen H M Prehn
Heinrich J Huber
Caoimhín G Concannon
Elaine W Kay
Deborah McNamara
Frank Murray
Patrick Dicker
Niamh McCawley
Joan Kehoe
Jasmin Schmid
and 2 others

Subjects

Medicine & Nursing

Topics
neoplasm staging apoptosis biological markers drug effects models biological caspases systems biology humans treatment outcome decision support techniques female therapeutic use drug therapy antimetabolites antineoplastic molecular targeted therapy fluorouracil principal component analysis metabolism colorectal neoplasms pathology logistic models chemotherapy adjuvant male physiopathology physiology middle aged aged

Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy. (2011)

Abstract 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. 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. 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. 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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Jochen H M Prehn, Heinrich J Huber, Caoimhín G Concannon, Elaine W Kay, Deborah McNamara, Frank Murray, Patrick Dicker, Niamh McCawley, Joan Kehoe, Jasmin Schmid and 2 others

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Heinrich J Huber
Royal College of Surgeons in Ireland
Total Publications: 39
 
3
Caoimhín G Concannon
Royal College of Surgeons in Ireland
Total Publications: 46
 
4
Elaine W Kay
Royal College of Surgeons in Ireland
Total Publications: 157
 
5
Deborah A McNamara
Royal College of Surgeons in Ireland
Total Publications: 17
 
6
F E Murray
Royal College of Surgeons in Ireland
 
7
Patrick Dicker
Royal College of Surgeons in Ireland
Total Publications: 95
 
8
Niamh McCawley
Royal College of Surgeons in Ireland
Total Publications: 9
 
9
Jasmin Schmid
Royal College of Surgeons in Ireland
Total Publications: 13