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000275260 1001_ $$aKeller, Kaylee M$$b0
000275260 245__ $$aThe potential of PARP as a therapeutic target across pediatric solid malignancies.
000275260 260__ $$aHeidelberg$$bSpringer$$c2023
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000275260 520__ $$aPediatric cancer is the leading cause of disease-related death in children and the need for better therapeutic options remains urgent. Due to the limited number of patients, target and drug development for pediatrics is often supplemented by data from studies focused on adult cancers. Recent evidence shows that pediatric cancers possess different vulnerabilities that should be explored independently from adult cancers.Using the publicly available Genomics of Drug Sensitivity in Cancer database, we explore therapeutic targets and biomarkers specific to the pediatric solid malignancies Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. Results are validated using cell viability assays and high-throughput drug screens are used to identify synergistic combinations.Using published drug screening data, PARP is identified as a drug target of interest across multiple different pediatric malignancies. We validate these findings, and we show that efficacy can be improved when combined with conventional chemotherapeutics, namely topoisomerase inhibitors. Additionally, using gene set enrichment analysis, we identify ribosome biogenesis as a potential biomarker for PARP inhibition in pediatric cancer cell lines.Collectively, our results provide evidence to support the further development of PARP inhibition and the combination with TOP1 inhibition as a therapeutic approach in solid pediatric malignancies. Additionally, we propose ribosome biogenesis as a component to PARP inhibitor sensitivity that should be further investigated to help maximize the potential utility of PARP inhibition and combinations across pediatric solid malignancies.
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000275260 650_7 $$2Other$$aDNA damage
000275260 650_7 $$2Other$$aPARP
000275260 650_7 $$2Other$$aPediatric cancer
000275260 650_7 $$2Other$$aReplication stress
000275260 650_7 $$2Other$$aRibosomes
000275260 650_7 $$2Other$$aSynergy
000275260 7001_ $$aKoetsier, Joost$$b1
000275260 7001_ $$aSchild, Linda$$b2
000275260 7001_ $$aAmo-Addae, Vicky$$b3
000275260 7001_ $$aEising, Selma$$b4
000275260 7001_ $$avan den Handel, Kim$$b5
000275260 7001_ $$aOber, Kimberley$$b6
000275260 7001_ $$aKoopmans, Bianca$$b7
000275260 7001_ $$aEssing, Anke$$b8
000275260 7001_ $$avan den Boogaard, Marlinde L$$b9
000275260 7001_ $$aLangenberg, Karin P S$$b10
000275260 7001_ $$0P:(DE-He78)bff9e3e3d86865d2b0836bb8f3ce98f3$$aJäger, Natalie$$b11$$udkfz
000275260 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b12$$udkfz
000275260 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b13$$udkfz
000275260 7001_ $$aDolman, M Emmy M$$b14
000275260 7001_ $$aMolenaar, Jan J$$b15
000275260 7001_ $$avan Hooff, Sander R$$b16
000275260 773__ $$0PERI:(DE-600)2041352-X$$a10.1186/s12885-022-10319-7$$gVol. 23, no. 1, p. 310$$n1$$p310$$tBMC cancer$$v23$$x1471-2407$$y2023
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