A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts.
Antineoplastic Agents
/ pharmacology
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Biomarkers, Tumor
/ genetics
Carcinoma, Ovarian Epithelial
/ drug therapy
Drug Resistance, Neoplasm
/ drug effects
Female
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Molecular Targeted Therapy
/ methods
Ovarian Neoplasms
/ drug therapy
Precision Medicine
Proof of Concept Study
Xenograft Model Antitumor Assays
/ methods
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 10 2020
01 10 2020
Historique:
received:
03
01
2020
revised:
29
04
2020
accepted:
29
07
2020
pubmed:
5
8
2020
medline:
13
2
2021
entrez:
5
8
2020
Statut:
ppublish
Résumé
Advanced ovarian cancers are a leading cause of cancer-related death in women and are currently treated with surgery and chemotherapy. This standard of care is often temporarily successful but exhibits a high rate of relapse, after which, treatment options are few. Here we investigate whether biomarker-guided use of multiple targeted therapies, including small molecules and antibody-drug conjugates, is a viable alternative. A panel of patient-derived ovarian cancer xenografts (PDX), similar in genetics and chemotherapy responsiveness to human tumors, was exposed to 21 monotherapies and combination therapies. Three monotherapies and one combination were found to be active in different subsets of PDX. Analysis of gene expression data identified biomarkers associated with responsiveness to each of the three targeted therapies, none of which directly inhibits an oncogenic driver. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. The distribution of biomarker positivity in The Cancer Genome Atlas data suggests the potential for a similar precision approach in human patients. SIGNIFICANCE: This study exploits a panel of patient-derived xenografts to demonstrate that most ovarian tumors can be matched to effective biomarker-guided treatments.
Identifiants
pubmed: 32747364
pii: 0008-5472.CAN-19-3850
doi: 10.1158/0008-5472.CAN-19-3850
pmc: PMC7541581
mid: NIHMS1618246
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4278-4287Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM007753
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA225088
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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