• Je něco špatně v tomto záznamu ?

Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor

AD. Woods, NE. Berlow, MV. Ortiz, F. Dela Cruz, A. Siddiquee, DF. Coutinho, R. Purohit, KET. Freier, JE. Michalek, M. Lathara, K. Matlock, G. Srivivasa, B. Royer-Pokora, R. Veselska, AL. Kung, C. Keller

. 2022 ; 69 (2) : e29401. [pub] 20211024

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22019449

Grantová podpora
P30 CA008748 NCI NIH HHS - United States
K12 CA184746 NCI NIH HHS - United States

BACKGROUND: Wilms tumor is the most common childhood kidney cancer. Two distinct histological subtypes of Wilms tumor have been described: tumors lacking anaplasia (the favorable subtype) and tumors displaying anaplastic features (the unfavorable subtype). Children with favorable disease generally have a very good prognosis, whereas those with anaplasia are oftentimes refractory to standard treatments and suffer poor outcomes, leading to an unmet clinical need. MYCN dysregulation has been associated with a number of pediatric cancers including Wilms tumor. PROCEDURES: In this context, we undertook a functional genomics approach to uncover novel therapeutic strategies for those patients with anaplastic Wilms tumor. Genomic analysis and in vitro experimentation demonstrate that cell growth can be reduced by modulating MYCN overexpression via bromodomain 4 (BRD4) inhibition in both anaplastic and nonanaplastic Wilms tumor models. RESULTS: We observed a time-dependent reduction of MYCN and MYCC protein levels upon BRD4 inhibition in Wilms tumor cell lines, which led to cell death and proliferation suppression. BRD4 inhibition significantly reduced tumor volumes in Wilms tumor patient-derived xenograft (PDX) mouse models. CONCLUSIONS: We suggest that AZD5153, a novel dual-BRD4 inhibitor, can reduce MYCN levels in both anaplastic and nonanaplastic Wilms tumor cell lines, reduces tumor volume in Wilms tumor PDXs, and should be further explored for its therapeutic potential.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22019449
003      
CZ-PrNML
005      
20220804135653.0
007      
ta
008      
220720s2022 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1002/pbc.29401 $2 doi
035    __
$a (PubMed)34693628
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Woods, Andrew D $u Children's Cancer Therapy Development Institute, Beaverton, Oregon, USA $1 https://orcid.org/0000000270364796
245    10
$a Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor / $c AD. Woods, NE. Berlow, MV. Ortiz, F. Dela Cruz, A. Siddiquee, DF. Coutinho, R. Purohit, KET. Freier, JE. Michalek, M. Lathara, K. Matlock, G. Srivivasa, B. Royer-Pokora, R. Veselska, AL. Kung, C. Keller
520    9_
$a BACKGROUND: Wilms tumor is the most common childhood kidney cancer. Two distinct histological subtypes of Wilms tumor have been described: tumors lacking anaplasia (the favorable subtype) and tumors displaying anaplastic features (the unfavorable subtype). Children with favorable disease generally have a very good prognosis, whereas those with anaplasia are oftentimes refractory to standard treatments and suffer poor outcomes, leading to an unmet clinical need. MYCN dysregulation has been associated with a number of pediatric cancers including Wilms tumor. PROCEDURES: In this context, we undertook a functional genomics approach to uncover novel therapeutic strategies for those patients with anaplastic Wilms tumor. Genomic analysis and in vitro experimentation demonstrate that cell growth can be reduced by modulating MYCN overexpression via bromodomain 4 (BRD4) inhibition in both anaplastic and nonanaplastic Wilms tumor models. RESULTS: We observed a time-dependent reduction of MYCN and MYCC protein levels upon BRD4 inhibition in Wilms tumor cell lines, which led to cell death and proliferation suppression. BRD4 inhibition significantly reduced tumor volumes in Wilms tumor patient-derived xenograft (PDX) mouse models. CONCLUSIONS: We suggest that AZD5153, a novel dual-BRD4 inhibitor, can reduce MYCN levels in both anaplastic and nonanaplastic Wilms tumor cell lines, reduces tumor volume in Wilms tumor PDXs, and should be further explored for its therapeutic potential.
650    _2
$a anaplazie $x genetika $7 D000708
650    _2
$a zvířata $7 D000818
650    _2
$a proteiny buněčného cyklu $x genetika $x metabolismus $7 D018797
650    _2
$a dítě $7 D002648
650    _2
$a down regulace $7 D015536
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a lidé $7 D006801
650    12
$a nádory ledvin $x farmakoterapie $x genetika $x metabolismus $7 D007680
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a myši $7 D051379
650    _2
$a protoonkogen n-myc $x genetika $7 D000071447
650    _2
$a jaderné proteiny $x genetika $7 D009687
650    _2
$a transkripční faktory $x genetika $x metabolismus $7 D014157
650    12
$a Wilmsův nádor $x farmakoterapie $x genetika $x metabolismus $7 D009396
655    _2
$a časopisecké články $7 D016428
655    _2
$a Research Support, N.I.H., Extramural $7 D052061
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Berlow, Noah E $u Children's Cancer Therapy Development Institute, Beaverton, Oregon, USA
700    1_
$a Ortiz, Michael V $u Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA $1 https://orcid.org/000000019379314X
700    1_
$a Dela Cruz, Filemon $u Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
700    1_
$a Siddiquee, Armaan $u Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
700    1_
$a Coutinho, Diego F $u Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
700    1_
$a Purohit, Reshma $u Children's Cancer Therapy Development Institute, Beaverton, Oregon, USA
700    1_
$a Freier, Katherine E Tranbarger $u Children's Cancer Therapy Development Institute, Beaverton, Oregon, USA
700    1_
$a Michalek, Joel E $u Department of Population Health Sciences, Joe R. & Teresa Lozano Long School of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA
700    1_
$a Lathara, Melvin $u Omics Data Automation Inc., Beaverton, Oregon, USA
700    1_
$a Matlock, Kevin $u Omics Data Automation Inc., Beaverton, Oregon, USA
700    1_
$a Srivivasa, Ganapati $u Omics Data Automation Inc., Beaverton, Oregon, USA
700    1_
$a Royer-Pokora, Brigitte $u Institute of Human Genetics, Medical Faculty, Heinrich Heine University Duesseldorf, Duesseldorf, Germany $1 https://orcid.org/0000000151147801
700    1_
$a Veselska, Renata $u Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000200489913 $7 mzk2003196540
700    1_
$a Kung, Andrew L $u Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
700    1_
$a Keller, Charles $u Children's Cancer Therapy Development Institute, Beaverton, Oregon, USA $1 https://orcid.org/0000000325057487
773    0_
$w MED00181047 $t Pediatric blood & cancer $x 1545-5017 $g Roč. 69, č. 2 (2022), s. e29401
856    41
$u https://pubmed.ncbi.nlm.nih.gov/34693628 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220720 $b ABA008
991    __
$a 20220804135647 $b ABA008
999    __
$a ok $b bmc $g 1822872 $s 1170692
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2022 $b 69 $c 2 $d e29401 $e 20211024 $i 1545-5017 $m Pediatric blood & cancer $n Pediatr Blood Cancer $x MED00181047
GRA    __
$a P30 CA008748 $p NCI NIH HHS $2 United States
GRA    __
$a K12 CA184746 $p NCI NIH HHS $2 United States
LZP    __
$a Pubmed-20220720

Najít záznam

Citační ukazatele

Možnosti archivace