Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy
- Suzanne Hector1,2,
- Markus Rehm1,2,
- Jasmin Schmid1,2,
- Joan Kehoe1,3,
- Niamh McCawley1,3,
- Patrick Dicker4,
- Frank Murray5,
- Deborah McNamara3,
- Elaine W Kay6,
- Caoimhin G Concannon1,2,
- Heinrich J Huber1,2,
- Jochen H M Prehn1,2
- 1Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
- 2Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland
- 3Department of Surgery, Beaumont Hospital, Dublin 9, Ireland
- 4Division of Population Health Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland
- 5Department of Gastroenterology, Beaumont Hospital, Dublin 9, Ireland
- 6Department of Pathology, Beaumont Hospital, Dublin 9, Ireland
- Correspondence to Professor Jochen H M Prehn, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland;
Contributors SH: study concept and design, acquisition of data, statistical analysis, analysis and interpretation of data, drafting of manuscript, critical revision of manuscript for content; MR: analysis and interpretation of data; drafting of manuscript, obtained funding; JS: statistical analysis, analysis and interpretation of data; JK: collection of clinical data; NM: collection of clinical data; PD: statistical analysis and interpretation; FM: collection of clinical material, critical revision of manuscript for content; DM: collection of clinical material and data, critical revision of manuscript for content; EWK: collection of clinical material and data, critical revision of manuscript for content; CGC: interpretation of data, critical revision of manuscript for content; HJH: study design, data analysis and interpretation; critical revision of manuscript for content; JHMP: conception, design and coordination of study, drafting of manuscript, critical revision of manuscript for content, obtained funding, final approval of the version to be published.
- Revised 15 September 2011
- Accepted 2 October 2011
- Published Online First 14 November 2011
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.
- colorectal cancer
- medical systems biology
- cell death
- cell biology
- heat shock proteins
- colonic diseases
- molecular biology
See Commentary, p 637
Funding This research was generously supported by grants from the Health Research Board (APOCOLON; TRA/2007/26) to JHMP and EWK, the European Union (FP7-Health, 200767-APO-SYS) to JHMP, Science Foundation Ireland (08/IN.1/B1949) to JHMP and HJH, and a grant from the Health Research Board (RP/2008/7) to MR.
Competing interests None.
Ethics approval Beaumont Hospital (Ethics) Medical Research Committee.
Provenance and peer review Not commissioned; externally peer reviewed.