Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma.
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Cerebellar Neoplasms
/ drug therapy
Child
Dactinomycin
/ pharmacology
Gene Expression Regulation, Neoplastic
High-Throughput Screening Assays
Humans
Male
Medulloblastoma
/ drug therapy
Mice, Inbred NOD
Mutation
Polymorphism, Single Nucleotide
Precision Medicine
/ methods
Exome Sequencing
Xenograft Model Antitumor Assays
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 12 2020
01 12 2020
Historique:
received:
22
05
2020
revised:
04
09
2020
accepted:
07
10
2020
pubmed:
14
10
2020
medline:
6
3
2021
entrez:
13
10
2020
Statut:
ppublish
Résumé
Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.
Identifiants
pubmed: 33046443
pii: 0008-5472.CAN-20-1655
doi: 10.1158/0008-5472.CAN-20-1655
pmc: PMC7718387
mid: NIHMS1637823
doi:
Substances chimiques
Antineoplastic Agents
0
Dactinomycin
1CC1JFE158
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
5393-5407Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM074024
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA248457
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA030199
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA184898
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS096368
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA220341
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023100
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217885
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA194107
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA159859
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009285
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA209891
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2020 American Association for Cancer Research.
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