Implementing Systems Modelling and Molecular Imaging to Predict the Efficacy of BCL-2 Inhibition in Colorectal Cancer Patient-Derived Xenograft Models.

ABT-199 BCL-2 FOLFOX PDX Venetoclax colorectal cancer deterministic modelling preclinical imaging radiomics systems biology

Journal

Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829

Informations de publication

Date de publication:
14 Oct 2020
Historique:
received: 16 09 2020
accepted: 09 10 2020
entrez: 17 10 2020
pubmed: 18 10 2020
medline: 18 10 2020
Statut: epublish

Résumé

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.

Identifiants

pubmed: 33066609
pii: cancers12102978
doi: 10.3390/cancers12102978
pmc: PMC7602510
pii:
doi:

Types de publication

Journal Article

Langues

eng

Subventions

Organisme : Health Research Board
ID : HRA-POR-2014-547
Pays : Ireland
Organisme : Science Foundation Ireland
ID : 13/IA/1881
Pays : Ireland
Organisme : Science Foundation Ireland
ID : 14/IA/2582
Pays : Ireland
Organisme : Science Foundation Ireland
ID : 13/CDA/2183
Pays : Ireland
Organisme : H2020 Societal Challenges
ID : 754923
Organisme : H2020 Research Infrastructures
ID : 731105
Organisme : Irish Cancer Society
ID : CCRC13GAL
Organisme : Science Foundation Ireland
ID : 15/IA/3104
Pays : Ireland
Organisme : Science Foundation Ireland
ID : 18/SPP/3522
Pays : Ireland
Organisme : Science Foundation Ireland
ID : 13/RC/2073
Pays : Ireland
Organisme : KWF Kankerbestrijding
ID : 12085/2018-2
Organisme : TRANSCAN Joint Transnational Call 2016
ID : UM 2017-8295

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Auteurs

Alice C O'Farrell (AC)

Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Monika A Jarzabek (MA)

Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Andreas U Lindner (AU)

Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Steven Carberry (S)

Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Emer Conroy (E)

UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland.

Ian S Miller (IS)

Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Kate Connor (K)

Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Liam Shiels (L)

Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Eugenia R Zanella (ER)

Candiolo Cancer Institute-FPO IRCCS, Candiolo, 10060 Torino, Italy.
Department of Oncology, University of Torino, Candiolo, 10060 Torino, Italy.

Federico Lucantoni (F)

Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Adam Lafferty (A)

Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Kieron White (K)

Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Mariangela Meyer Meyer Villamandos (MM)

Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Patrick Dicker (P)

Department of Epidemiology and Public Health Medicine, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

William M Gallagher (WM)

UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland.

Simon A Keek (SA)

The D-Lab, Department of Precision Medicine, GROW-School for Oncology, Maastricht University, 6229 ER Maastricht, The Netherlands.

Sebastian Sanduleanu (S)

The D-Lab, Department of Precision Medicine, GROW-School for Oncology, Maastricht University, 6229 ER Maastricht, The Netherlands.

Philippe Lambin (P)

The D-Lab, Department of Precision Medicine, GROW-School for Oncology, Maastricht University, 6229 ER Maastricht, The Netherlands.
Department of Radiology and Nuclear Imaging, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands.

Henry C Woodruff (HC)

The D-Lab, Department of Precision Medicine, GROW-School for Oncology, Maastricht University, 6229 ER Maastricht, The Netherlands.
Department of Radiology and Nuclear Imaging, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands.

Andrea Bertotti (A)

Candiolo Cancer Institute-FPO IRCCS, Candiolo, 10060 Torino, Italy.
Department of Oncology, University of Torino, Candiolo, 10060 Torino, Italy.

Livio Trusolino (L)

Candiolo Cancer Institute-FPO IRCCS, Candiolo, 10060 Torino, Italy.
Department of Oncology, University of Torino, Candiolo, 10060 Torino, Italy.

Annette T Byrne (AT)

Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland.

Jochen H M Prehn (JHM)

Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland.

Classifications MeSH