Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma.
Animals
Antineoplastic Agents
/ pharmacology
Biomarkers, Tumor
Cerebellar Neoplasms
/ drug therapy
Computational Biology
/ methods
Disease Models, Animal
Drug Development
Drug Evaluation, Preclinical
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
/ drug effects
Gene Regulatory Networks
Humans
Medulloblastoma
/ drug therapy
Mice
Mice, Transgenic
Pharmacogenetics
/ methods
Protein Interaction Mapping
Protein Interaction Maps
Systems Biology
/ methods
Transcriptome
Xenograft Model Antitumor Assays
Drug target
Genetic screen
Medulloblastoma
Microtubule stabilization
Protein interaction network
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
21 06 2021
21 06 2021
Historique:
received:
23
07
2020
accepted:
04
06
2021
entrez:
22
6
2021
pubmed:
23
6
2021
medline:
17
2
2022
Statut:
epublish
Résumé
Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects. We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB. Our analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB. Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.
Sections du résumé
BACKGROUND
Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects.
METHODS
We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB.
RESULTS
Our analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB.
CONCLUSIONS
Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.
Identifiants
pubmed: 34154646
doi: 10.1186/s13073-021-00920-z
pii: 10.1186/s13073-021-00920-z
pmc: PMC8215804
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
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
103Subventions
Organisme : NCI NIH HHS
ID : RO1 CA112250
Pays : United States
Organisme : NCI NIH HHS
ID : RO1 CA135491
Pays : United States
Références
Cancer Res. 2002 Jan 15;62(2):466-71
pubmed: 11809697
Cancer Cell. 2017 Jun 12;31(6):737-754.e6
pubmed: 28609654
Am J Obstet Gynecol. 2013 Jul;209(1):62.e1-9
pubmed: 23583215
J Clin Oncol. 2011 Apr 10;29(11):1408-14
pubmed: 20823417
Cancer Chemother Pharmacol. 2015 Nov;76(5):1013-24
pubmed: 26416565
Oncotarget. 2014 May 15;5(9):2355-71
pubmed: 24796395
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D668-72
pubmed: 16381955
Drugs. 2009 Jul 30;69(11):1471-81
pubmed: 19634925
Cancer Res. 2008 Sep 1;68(17):7050-8
pubmed: 18757419
Nat Med. 2014 Jul;20(7):732-40
pubmed: 24973920
Pharmgenomics Pers Med. 2013 Dec 31;7:21-9
pubmed: 24516336
Nat Rev Dis Primers. 2019 Feb 14;5(1):11
pubmed: 30765705
Cancer Res. 2020 Dec 1;80(23):5393-5407
pubmed: 33046443
Nat Commun. 2019 Jun 3;10(1):2400
pubmed: 31160565
Clin Cancer Res. 2014 Oct 15;20(20):5281-9
pubmed: 25107917
Cancer Res. 2007 Jun 1;67(11):5425-33
pubmed: 17545624
Cancer Cell. 2016 Mar 14;29(3):311-323
pubmed: 26977882
Genome Med. 2014 Jul 30;6(7):57
pubmed: 25165489
J Clin Oncol. 2006 Apr 20;24(12):1924-31
pubmed: 16567768
Nat Rev Drug Discov. 2010 Sep;9(9):677-8
pubmed: 20811375
Cancer Res. 2008 May 1;68(9):3161-8
pubmed: 18451141
Clin Cancer Res. 2016 Aug 1;22(15):3903-14
pubmed: 27012813
Neuro Oncol. 2015 Jan;17(1):107-15
pubmed: 25140037
PLoS One. 2008 Aug 28;3(8):e3088
pubmed: 18769486
Lancet Oncol. 2006 Oct;7(10):813-20
pubmed: 17012043
Nature. 2012 Aug 2;488(7409):100-5
pubmed: 22832583
Curr Opin Oncol. 2013 Nov;25(6):674-81
pubmed: 24076581
Cancer. 2013 Jul 15;119(14):2582-92
pubmed: 23585021
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Acta Neuropathol. 2012 Apr;123(4):465-72
pubmed: 22134537
J Clin Oncol. 2005 Nov 1;23(31):7951-7
pubmed: 16258095
N Engl J Med. 2005 Mar 10;352(10):978-86
pubmed: 15758008
Breast Cancer. 2017 Mar;24(2):171-179
pubmed: 27491426
Mol Cancer Ther. 2006 Oct;5(10):2435-43
pubmed: 17041086
Clin Cancer Res. 2017 Oct 1;23(19):5802-5813
pubmed: 28637687
Health (Irvine Calif). 2013 May;5(5A):
pubmed: 24224072
Neuro Oncol. 2010 Oct;12(10):1043-9
pubmed: 20501632
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9758-63
pubmed: 17537913
Int J Mol Sci. 2017 Jul 04;18(7):
pubmed: 28677634
Cancer Cell. 2015 Jan 12;27(1):72-84
pubmed: 25533335
Clin Cancer Res. 2013 Nov 15;19(22):6305-12
pubmed: 24077351
J Vis Exp. 2016 Nov 17;(117):
pubmed: 27911396
Neuro Oncol. 2011 Sep;13(9):1000-10
pubmed: 21743064
N Engl J Med. 2012 Nov 8;367(19):1783-91
pubmed: 23020162
Neuro Oncol. 2004 Oct;6(4):300-5
pubmed: 15494097
Clin Cancer Res. 2014 Feb 15;20(4):912-25
pubmed: 24297863
Nature. 2012 Aug 2;488(7409):106-10
pubmed: 22820256
Nature. 2001 May 3;411(6833):41-2
pubmed: 11333967
J Clin Oncol. 2015 Aug 20;33(24):2646-54
pubmed: 26169613
J Biol Chem. 2004 Sep 17;279(38):39431-7
pubmed: 15262986
Nat Rev Clin Oncol. 2011 Jun 28;8(9):540-9
pubmed: 21709698
PLoS One. 2015 Mar 18;10(3):e0119834
pubmed: 25785590
Nat Med. 2018 Nov;24(11):1752-1761
pubmed: 30349086
J Clin Oncol. 2011 Apr 10;29(11):1424-30
pubmed: 21098324
Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):E4325-34
pubmed: 24167280
J Clin Oncol. 2006 Sep 1;24(25):4202-8
pubmed: 16943538
Lung Cancer. 2012 Mar;75(3):306-12
pubmed: 21996087
Nat Methods. 2012 Apr;9(4):345-50
pubmed: 22453911
Cancer Res. 2013 Oct 15;73(20):6310-22
pubmed: 24067506
Nature. 2012 Aug 2;488(7409):49-56
pubmed: 22832581