Royal College of Surgeons in Ireland
O'Farrell et al cancers-12- 2020.pdf (1.27 MB)

Implementing systems modelling and molecular imaging to predict the efficacy of BCL-2 inhibition in colorectal cancer patient-derived xenograft models.

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journal contribution
posted on 2020-10-23, 13:03 authored by Alice O'FarrellAlice O'Farrell, Monika Jarzabek, Andreas Ulrich Lindner, Steven Carberry, Emer Conroy, Ian Miller, Kate Connor, Liam ShielsLiam Shiels, Eugenia R. Zanella, Federico Lucantoni, Adam Lafferty, Kieron White, Mariangela Meyer Villamandos, Patrick DickerPatrick Dicker, William M Gallagher, Simon A. Keek, Sebastian Sanduleanu, Philippe Lambin, Henry C. Woodruff, Andrea Bertotti, Livio Trusolino, Annette ByrneAnnette Byrne, Jochen PrehnJochen Prehn
Resistance to chemotherapy often results from dysfunctional apoptosis, however multiple proteins with overlapping functions regulate this pathway. We sought to determine whether an extensively validated, deterministic apoptosis systems model, ‘DR_MOMP’, could be used as a stratification tool for the apoptosis sensitiser and BCL-2 antagonist, ABT-199 in patient-derived xenograft (PDX) models of colorectal cancer (CRC). Through quantitative profiling of BCL-2 family proteins, we identified two PDX models which were predicted by DR_MOMP to be sufficiently sensitive to 5-fluorouracil (5-FU)-based chemotherapy (CRC0344), or less responsive to chemotherapy but sensitised by ABT-199 (CRC0076). Treatment with ABT-199 significantly improved responses of CRC0076 PDXs to 5-FU-based chemotherapy, but showed no sensitisation in CRC0344 PDXs, as predicted from systems modelling. 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scans were performed to investigate possible early biomarkers of response. In CRC0076, a significant post-treatment decrease in mean standard uptake value was indeed evident only in the combination treatment group. Radiomic CT feature analysis of pre-treatment images in CRC0076 and CRC0344 PDXs identified features which could phenotypically discriminate between models, but were not predictive of treatment responses. Collectively our data indicate that systems modelling may identify metastatic (m)CRC patients benefitting from ABT-199, and that 18F-FDG-PET could independently support such predictions.


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Data Availability Statement


The original article is available at

Published Citation

O’Farrell AC, Jarzabek MA, Lindner AU, Carberry S, Conroy E. Miller IS, Connor K, Shiels L, Zanella ER, Lucantoni F, Lafferty A, White K, Meyer Villamandos M, Dicker P, Gallagher WM, Keek SA, Sanduleanu S, Lambin P, Woodruff HC, Bertotti A, Trusolino L, Byrne AT, Prehn JHM. Implementing systems modelling and molecular imaging to predict the efficacy of BCL-2 inhibition in colorectal cancer patient-derived xenograft models. Cancers 2020;12: 2978.

Publication Date

14 October 2020

PubMed ID



  • Physiology and Medical Physics
  • Public Health and Epidemiology

Research Area

  • Cancer




  • Published Version (Version of Record)