@article{d0956dd4d0f647fba40560f9cce46633,
title = "Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor",
abstract = "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.",
author = "Woods, {Andrew D.} and Berlow, {Noah E.} and Ortiz, {Michael V.} and {Dela Cruz}, Filemon and Armaan Siddiquee and Coutinho, {Diego F.} and Reshma Purohit and Freier, {Katherine E.Tranbarger} and Michalek, {Joel E.} and Melvin Lathara and Kevin Matlock and Ganapati Srivivasa and Brigitte Royer-Pokora and Renata Veselska and Kung, {Andrew L.} and Charles Keller",
note = "Funding Information: Rally and CURE Childhood Cancer Foundations; The Truth 365; Infinite Love for Kids Fighting Cancer; Joey's Wings; Alex's Army; Unravel Pediatric Cancer; The Bozeman 3; Hope from Harper; Cancer Center Support, Grant Number: P30 CA008748; The Paulie Strong Foundation; The Grayson Fund; Willens Family Fund; Hyundai Hope on Wheels; Cannonball Kids Cancer; Cookies for Kids Cancer; The Starr Cancer Consortium; Conquer Cancer; ASCO Foundation, Grant Number: NCI K12 CA184746; Sam Day Foundation; Childhood Cancer Project Funding Information: This work was supported by research grants from the Rally and CURE Childhood Cancer Foundations, The Truth 365, Infinite Love for Kids Fighting Cancer, Joey's Wings, Alex's Army, Unravel Pediatric Cancer, The Bozeman 3, Hope from Harper, Cancer Center Support Grant P30 CA008748, The Paulie Strong Foundation, The Grayson Fund, the Willens Family Fund, Hyundai Hope on Wheels, Cannonball Kids Cancer, Cookies for Kids Cancer, The Starr Cancer Consortium, Conquer Cancer, the ASCO Foundation, NCI K12 CA184746, and the Wilms tumor patient/family community. The CuReFAST tumor banking program is supported by the Sam Day Foundation and the Childhood Cancer Project. This study is dedicated to Stellablue, anaplastic Wilms tumor survivor. We are grateful to Dr. Herman Yeger (Sick Kids Hospital, Toronto, Canada), Dr. Renata Veselska (Masaryk University, Brno, Czech Republic), Dr. Peter Houghton (Greehey Children's Cancer Research Institute, TX, USA), and the Children's Oncology Group Cell Culture/Xenograft Repository (CCCells.org) for providing samples. Thank you to Dr. Naomi Pode‐Shakkad for inspiration, support, and helpful discussion. Funding Information: informationRally and CURE Childhood Cancer Foundations; The Truth 365; Infinite Love for Kids Fighting Cancer; Joey's Wings; Alex's Army; Unravel Pediatric Cancer; The Bozeman 3; Hope from Harper; Cancer Center Support, Grant Number: P30 CA008748; The Paulie Strong Foundation; The Grayson Fund; Willens Family Fund; Hyundai Hope on Wheels; Cannonball Kids Cancer; Cookies for Kids Cancer; The Starr Cancer Consortium; Conquer Cancer; ASCO Foundation, Grant Number: NCI K12 CA184746; Sam Day Foundation; Childhood Cancer ProjectThis work was supported by research grants from the Rally and CURE Childhood Cancer Foundations, The Truth 365, Infinite Love for Kids Fighting Cancer, Joey's Wings, Alex's Army, Unravel Pediatric Cancer, The Bozeman 3, Hope from Harper, Cancer Center Support Grant P30 CA008748, The Paulie Strong Foundation, The Grayson Fund, the Willens Family Fund, Hyundai Hope on Wheels, Cannonball Kids Cancer, Cookies for Kids Cancer, The Starr Cancer Consortium, Conquer Cancer, the ASCO Foundation, NCI K12 CA184746, and the Wilms tumor patient/family community. The CuReFAST tumor banking program is supported by the Sam Day Foundation and the Childhood Cancer Project. This study is dedicated to Stellablue, anaplastic Wilms tumor survivor. We are grateful to Dr. Herman Yeger (Sick Kids Hospital, Toronto, Canada), Dr. Renata Veselska (Masaryk University, Brno, Czech Republic), Dr. Peter Houghton (Greehey Children's Cancer Research Institute, TX, USA), and the Children's Oncology Group Cell Culture/Xenograft Repository (CCCells.org) for providing samples. Thank you to Dr. Naomi Pode-Shakkad for inspiration, support, and helpful discussion. Publisher Copyright: {\textcopyright} 2021 Wiley Periodicals LLC",
year = "2022",
month = feb,
doi = "10.1002/pbc.29401",
language = "English (US)",
volume = "69",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "2",
}