TY - JOUR
T1 - The potential of PARP as a therapeutic target across pediatric solid malignancies
AU - Keller, Kaylee M.
AU - Koetsier, Joost
AU - Schild, Linda
AU - Amo-Addae, Vicky
AU - Eising, Selma
AU - van den Handel, Kim
AU - Ober, Kimberley
AU - Koopmans, Bianca
AU - Essing, Anke
AU - van den Boogaard, Marlinde L.
AU - Langenberg, Karin P. S.
AU - Jäger, Natalie
AU - Kool, Marcel
AU - Pfister, Stefan
AU - Dolman, M. Emmy M.
AU - Molenaar, Jan J.
AU - van Hooff, Sander R.
N1 - Funding Information: This project has received funding from the Innovative Medicines Initiative 2 Join Undertaking under Grant Agreement No116064 ( https://www.itccp4.eu ). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations. In addition, this project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program under grant agreement No. 716079 Predict. Lastly, this study was supported by the Dutch Cancer Foundation (KWF project number 8351) within the TRANSCAN-2 project “BRCAddict”. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Background: Pediatric 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. Methods: 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. Results: 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. Conclusion: 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.
AB - Background: Pediatric 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. Methods: 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. Results: 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. Conclusion: 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.
KW - DNA damage
KW - PARP
KW - Pediatric cancer
KW - Replication stress
KW - Ribosomes
KW - Synergy
UR - http://www.scopus.com/inward/record.url?scp=85151796307&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s12885-022-10319-7
DO - https://doi.org/10.1186/s12885-022-10319-7
M3 - Article
C2 - 37020198
SN - 1471-2407
VL - 23
JO - BMC Cancer
JF - BMC Cancer
IS - 1
M1 - 310
ER -