Bromodomain 4 inhibition leads to MYCN downregulation in Wilms
tumor

J 2022

Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor

WOODS, Andrew D.; Noah E. BERLOW; Michael V. ORTIZ; Filemon Dela CRUZ; Armaan SIDDIQUEE et al.

Základní údaje

Originální název

Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor

Autoři

Vydání

Pediatric Blood & Cancer, Wiley, 2022, 1545-5009

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.200

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14310/22:00125047

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

anaplasia; AZD5153; BRD4; MYCN; Wilms tumor

Štítky

14314010, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 12. 1. 2022 17:29, Mgr. Marie Novosadová Šípková, DiS.

Anotace

V originále

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.

Citovat

WOODS, Andrew D.; Noah E. BERLOW; Michael V. ORTIZ; Filemon Dela CRUZ; Armaan SIDDIQUEE; Diego F. COUTINHO; Reshma PUROHIT; Katherine E. TRANBARGER FREIER; Joel E. MICHALEK; Melvin LATHARA; Kevin MATLOCK; Ganapati SRIVIVASA; Brigitte ROYER-POKORA; Renata VESELSKÁ; Andrew L. KUNG a Charles KELLER. Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor. Pediatric Blood & Cancer. Wiley, 2022, roč. 69, č. 2, s. "e29401", 12 s. ISSN 1545-5009. Dostupné z: https://doi.org/10.1002/pbc.29401.

@article{1803573,
   author = {Woods, Andrew D. and Berlow, Noah E. and Ortiz, Michael V. and Cruz, Filemon Dela and Siddiquee, Armaan and Coutinho, Diego F. and Purohit, Reshma and Tranbarger Freier, Katherine E. and Michalek, Joel E. and Lathara, Melvin and Matlock, Kevin and Srivivasa, Ganapati and RoyerandPokora, Brigitte and Veselská, Renata and Kung, Andrew L. and Keller, Charles},
   article_number = {2},
   doi = {https://doi.org/10.1002/pbc.29401},
   keywords = {anaplasia; AZD5153; BRD4; MYCN; Wilms tumor},
   language = {eng},
   issn = {1545-5009},
   journal = {Pediatric Blood & Cancer},
   title = {Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor},
   url = {https://onlinelibrary.wiley.com/doi/full/10.1002/pbc.29401},
   volume = {69},
   year = {2022}
}

TY  - JOUR
ID  - 1803573
AU  - Woods, Andrew D. - Berlow, Noah E. - Ortiz, Michael V. - Cruz, Filemon Dela - Siddiquee, Armaan - Coutinho, Diego F. - Purohit, Reshma - Tranbarger Freier, Katherine E. - Michalek, Joel E. - Lathara, Melvin - Matlock, Kevin - Srivivasa, Ganapati - Royer-Pokora, Brigitte - Veselská, Renata - Kung, Andrew L. - Keller, Charles
PY  - 2022
TI  - Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor
JF  - Pediatric Blood & Cancer
VL  - 69
IS  - 2
SP  - "e29401"
EP  - "e29401"
PB  - Wiley
SN  - 15455009
KW  - anaplasia
KW  - AZD5153
KW  - BRD4
KW  - MYCN
KW  - Wilms tumor
UR  - https://onlinelibrary.wiley.com/doi/full/10.1002/pbc.29401
N2  - 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.
ER  -

WOODS, Andrew D.; Noah E. BERLOW; Michael V. ORTIZ; Filemon Dela CRUZ; Armaan SIDDIQUEE; Diego F. COUTINHO; Reshma PUROHIT; Katherine E. TRANBARGER FREIER; Joel E. MICHALEK; Melvin LATHARA; Kevin MATLOCK; Ganapati SRIVIVASA; Brigitte ROYER-POKORA; Renata VESELSKÁ; Andrew L. KUNG a Charles KELLER. Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor. \textit{Pediatric Blood \&{} Cancer}. Wiley, 2022, roč.~69, č.~2, s.~''e29401'', 12 s. ISSN~1545-5009. Dostupné z: https://doi.org/10.1002/pbc.29401.

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