Ex vivo culture of cells derived from circulating tumour cell xenograft to support small cell lung cancer research and experimental therapeutics.
Animals
Antineoplastic Agents
/ chemistry
Cell Proliferation
/ drug effects
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Humans
Indazoles
/ chemistry
Lung Neoplasms
/ drug therapy
Mice
Mice, Inbred Strains
Mice, SCID
Neoplasms, Experimental
/ drug therapy
Neoplastic Cells, Circulating
/ drug effects
Small Cell Lung Carcinoma
/ drug therapy
Structure-Activity Relationship
Sulfonamides
/ chemistry
Tumor Cells, Cultured
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
21
06
2018
revised:
26
09
2018
accepted:
04
10
2018
pubmed:
15
11
2018
medline:
25
2
2020
entrez:
15
11
2018
Statut:
ppublish
Résumé
Small cell lung cancer (SCLC) is an aggressive disease with median survival of <2 years. Tumour biopsies for research are scarce, especially from extensive-stage patients, with repeat sampling at disease progression rarely performed. We overcame this limitation for relevant preclinical models by developing SCLC circulating tumour cell derived explants (CDX), which mimic the donor tumour pathology and chemotherapy response. To facilitate compound screening and identification of clinically relevant biomarkers, we developed short-term ex vivo cultures of CDX tumour cells. CDX tumours were disaggregated, and the human tumour cells derived were cultured for a maximum of 5 weeks. Phenotypic, transcriptomic and pharmacological characterization of these cells was performed. CDX cultures maintained a neuroendocrine phenotype, and most changes in the expression of protein-coding genes observed in cultures, for up to 4 weeks, were reversible when the cells were re-implanted in vivo. Moreover, the CDX cultures exhibited a similar sensitivity to chemotherapy compared to the corresponding CDX tumour in vivo and were able to predict in vivo responses to therapeutic candidates. Short-term cultures of CDX provide a tractable platform to screen new treatments, identify predictive and pharmacodynamic biomarkers and investigate mechanisms of resistance to better understand the progression of this recalcitrant tumour.
Sections du résumé
BACKGROUND AND PURPOSE
Small cell lung cancer (SCLC) is an aggressive disease with median survival of <2 years. Tumour biopsies for research are scarce, especially from extensive-stage patients, with repeat sampling at disease progression rarely performed. We overcame this limitation for relevant preclinical models by developing SCLC circulating tumour cell derived explants (CDX), which mimic the donor tumour pathology and chemotherapy response. To facilitate compound screening and identification of clinically relevant biomarkers, we developed short-term ex vivo cultures of CDX tumour cells.
EXPERIMENTAL APPROACH
CDX tumours were disaggregated, and the human tumour cells derived were cultured for a maximum of 5 weeks. Phenotypic, transcriptomic and pharmacological characterization of these cells was performed.
KEY RESULTS
CDX cultures maintained a neuroendocrine phenotype, and most changes in the expression of protein-coding genes observed in cultures, for up to 4 weeks, were reversible when the cells were re-implanted in vivo. Moreover, the CDX cultures exhibited a similar sensitivity to chemotherapy compared to the corresponding CDX tumour in vivo and were able to predict in vivo responses to therapeutic candidates.
CONCLUSIONS AND IMPLICATIONS
Short-term cultures of CDX provide a tractable platform to screen new treatments, identify predictive and pharmacodynamic biomarkers and investigate mechanisms of resistance to better understand the progression of this recalcitrant tumour.
Identifiants
pubmed: 30427531
doi: 10.1111/bph.14542
pmc: PMC6329630
doi:
Substances chimiques
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
0
Antineoplastic Agents
0
Indazoles
0
Sulfonamides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
436-450Subventions
Organisme : Cancer Research UK Manchester Institute Core
ID : C5759/A20971
Pays : International
Organisme : Lung Cancer Centre of Excellence
ID : C5759/A20465
Pays : International
Informations de copyright
© 2018 The British Pharmacological Society.
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