Combinatorial screening using orthotopic patient derived xenograft-expanded early phase cultures of osteosarcoma identify novel therapeutic drug combinations.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Bone Neoplasms
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Dose-Response Relationship, Drug
Drug Repositioning
High-Throughput Screening Assays
Histone Deacetylase Inhibitors
/ pharmacology
Humans
Mice, Inbred NOD
Mice, SCID
Mice, Transgenic
Molecular Targeted Therapy
Osteosarcoma
/ drug therapy
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Proteasome Inhibitors
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Tumor Burden
/ drug effects
Xenograft Model Antitumor Assays
Osteosarcoma
high-throughput drug screening
histone deacetylase
inhibitors
orthotopic xenografts
Journal
Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053
Informations de publication
Date de publication:
01 02 2019
01 02 2019
Historique:
received:
05
08
2018
revised:
17
10
2018
accepted:
24
10
2018
pubmed:
6
11
2018
medline:
2
11
2019
entrez:
6
11
2018
Statut:
ppublish
Résumé
Lead discovery in osteosarcoma has been hampered by the lack of new agents, limited representative clinical samples and paucity of accurate preclinical models. We developed orthotopic patient-derived xenografts (PDXs) that recapitulated the molecular, cellular and histologic features of primary tumors, and screened PDX-expanded short-term cultures and commercial cell lines of osteosarcoma against focused drug libraries. Osteosarcoma cells were most sensitive to HDAC, proteasome, and combination PI3K/MEK and PI3K/mTOR inhibitors, and least sensitive to PARP, RAF, ERK and MEK inhibitors. Correspondingly, PI3K signaling pathway genes were up-regulated in metastatic tumors compared to primary tumors. In combinatorial screens, as a class, HDAC inhibitors showed additive effects when combined with standard-of-care agents gemcitabine and doxorubicin. This lead discovery strategy afforded a means to perform high-throughput drug screens of tumor cells that accurately recapitulated those from original human tumors, and identified classes of novel and repurposed drugs with activity against osteosarcoma.
Identifiants
pubmed: 30395907
pii: S0304-3835(18)30648-7
doi: 10.1016/j.canlet.2018.10.033
pmc: PMC6342199
mid: NIHMS1512968
pii:
doi:
Substances chimiques
Histone Deacetylase Inhibitors
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Proteasome Inhibitors
0
Protein Kinase Inhibitors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
262-270Subventions
Organisme : NEI NIH HHS
ID : R01 EY018599
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY014867
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA168875
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier B.V. All rights reserved.
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