The potential of PARP as a therapeutic target across pediatric solid malignancies

Abstract

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.

Therapeutic Targeting of DNA Repair Pathways in Pediatric Extracranial Solid Tumors: Current State and Implications for Immunotherapy

“…Fam et al demonstrated the single-agent activity of both TDP1 and PARP inhibition in RMS cell lines as well as the combined efficacy of either TDP1 or PARP inhibition with irinotecan analogues [139]. In another preclinical study, the PARP inhibitor talazoparib was found to be the most effective when combined with SN-38, the active metabolite of irinotecan, in RMS cell lines [142]. Additional preclinical work demonstrated that the Wee1 inhibitor AZD1775, alone and in combination with irinotecan or vincristine, led to G2/M phase arrest, increased DNA damage, and had anti-tumor activity against in vivo models of high-risk RMS [138,143].…”

Current Molecular and Clinical Landscape of ATRT – The Link to Future Therapies

“…Despite dismal treatment responses upon single agent use, recent investigations in pediatric solid tumors provide information on beneficial effects of PARP inhibitors combined with conventional chemotherapy, ie, alkylating agents or topoisomerase inhibitors. 116 …”