The potential role of the extracellular matrix in the activity of trabectedin in UPS and L-sarcoma: evidences from a patient-derived primary culture case series in tridimensional and zebrafish models.
3D scaffold
Chemotherapy
Extracellular matrix
Patient‐derived primary cultures
Trabectedin
Undifferentiated pleomorphic sarcoma and L-sarcoma
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
11 May 2021
11 May 2021
Historique:
received:
27
11
2020
accepted:
26
04
2021
entrez:
12
5
2021
pubmed:
13
5
2021
medline:
15
12
2021
Statut:
epublish
Résumé
Soft tissue sarcomas (STS) are a rare group of solid neoplasm including among others liposarcoma, leiomyosarcoma (L-sarcoma) and undifferentiated pleomorphic sarcoma (UPS) entities. The current first-line treatment is represented by anthracycline based- regimens, second-line may include trabectedin. Currently the activity of trabectedin and its mechanism of action is not completely elucidated. Taking the advantages of our 3D patient-derived primary culture translational model we performed genomic-, chemobiogram, proteomic- and in vivo analysis in a UPS culture (S1). Furthermore pharmacological profiling of a UPS and L-sarcoma patient-derived case series and in silico analysis were carried out. Trabectedin exhibited an increased activity in 3D respect to 2D cultures suggesting an extracellular matrix (ECM) and timp1 involvement in its mechanism of action. Moreover 3D S1 xenotranspanted zebrafish model showed an increased sensitivity to trabectedin. Finally the results were further validated in a UPS and L-sarcoma case series. Taken together these results confirmed the activity of trabectedin in these STS histotypes. Moreover the data underline the ECM involvement in the cytotoxic effect mediated by trabectedin and could open the door for researches aimed to focus on the patient setting that could benefit from this agent.
Sections du résumé
BACKGROUND
BACKGROUND
Soft tissue sarcomas (STS) are a rare group of solid neoplasm including among others liposarcoma, leiomyosarcoma (L-sarcoma) and undifferentiated pleomorphic sarcoma (UPS) entities. The current first-line treatment is represented by anthracycline based- regimens, second-line may include trabectedin. Currently the activity of trabectedin and its mechanism of action is not completely elucidated.
METHODS
METHODS
Taking the advantages of our 3D patient-derived primary culture translational model we performed genomic-, chemobiogram, proteomic- and in vivo analysis in a UPS culture (S1). Furthermore pharmacological profiling of a UPS and L-sarcoma patient-derived case series and in silico analysis were carried out.
RESULTS
RESULTS
Trabectedin exhibited an increased activity in 3D respect to 2D cultures suggesting an extracellular matrix (ECM) and timp1 involvement in its mechanism of action. Moreover 3D S1 xenotranspanted zebrafish model showed an increased sensitivity to trabectedin. Finally the results were further validated in a UPS and L-sarcoma case series.
CONCLUSIONS
CONCLUSIONS
Taken together these results confirmed the activity of trabectedin in these STS histotypes. Moreover the data underline the ECM involvement in the cytotoxic effect mediated by trabectedin and could open the door for researches aimed to focus on the patient setting that could benefit from this agent.
Identifiants
pubmed: 33975637
doi: 10.1186/s13046-021-01963-1
pii: 10.1186/s13046-021-01963-1
pmc: PMC8111914
doi:
Substances chimiques
Antineoplastic Agents, Alkylating
0
Trabectedin
ID0YZQ2TCP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
165Subventions
Organisme : Italian Ministry of Health
ID : Italian Ministry of Health
Organisme : Alleanza Contro il Cancro (ACC)
ID : Alleanza Contro il Cancro (ACC)
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