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
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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