title: Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Hector
authors.forename: Markus
authors.initials: M
authors.lastname: Rehm
authors.forename: Jasmin
authors.initials: J
authors.lastname: Schmid
authors.forename: Joan
authors.initials: J
authors.lastname: Kehoe
authors.forename: Niamh
authors.initials: N
authors.lastname: McCawley
authors.forename: Patrick
authors.initials: P
authors.lastname: Dicker
authors.forename: Frank
authors.initials: F
authors.lastname: Murray
authors.forename: Deborah
authors.initials: D
authors.lastname: McNamara
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Kay
authors.forename: Caoimhin G
authors.initials: CG
authors.lastname: Concannon
authors.forename: Heinrich J
authors.initials: HJ
authors.lastname: Huber
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003661:Decision Support Techniques; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D025341:Principal Component Analysis; D049490:Systems Biology; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D020169:Caspases; D005472:Fluorouracil