Targeting the DNA Repair Pathway in Ewing Sarcoma

Abstract

Ewing sarcoma (EWS) is a tumor of the bone and soft-tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis). PARPi-induced cytotoxicity in EWS cells was 10- to 1,000-fold higher after administration of the DNA-damaging agents irinotecan or temozolomide. We developed an orthotopic EWS mouse model and performed pharmacokinetic and pharmacodynamic studies using 3 different PARPis that are in clinical development for pediatric cancer. Irinotecan administered on a low-dose, protracted schedule previously optimized for pediatric patients was an effective DNA-damaging agent when combined with PARPis; it was also better tolerated than combinations with temozolomide. Combining PARPis with irinotecan and temozolomide gave complete and durable responses in more than 80% of the mice.

Trapping Poly(ADP-Ribose) Polymerase

“…In contrast, veliparib is ∼1000-to 10,000-fold less potent than talazoparib in cytotoxicity assays. Similar observations were obtained in other laboratories (Murai et al, 2012(Murai et al, , 2014aStewart et al, 2014). This magnitude of differences in the cytotoxicity cannot be explained simply by differences in catalytic inhibition.…”

PARP Inhibitors Sensitize Ewing Sarcoma Cells to Temozolomide-Induced Apoptosis via the Mitochondrial Pathway

“…These findings may have important clinical implications, because topoisomerase I poisons and DNA methylating agents such as TMZ are used in second-line chemotherapy regimens for Ewing sarcoma (22). However, increased host toxicity may limit the therapeutic window for such combinations, because there is preclinical and clinical evidence for enhanced normal tissue toxicity upon cotreatment with PARP inhibitors and TMZ or topoisomerase I inhibitors (12,16,25). PARP inhibitors also enhanced doxorubicin-, etoposide-, or ifosfamide-induced cytotoxicity in Ewing sarcoma cells, although less consistently.…”

“…CI values were then used to generate a heatmap of drug interactions according to the subclassification provided by the software's manual. to the role of PARP in the repair of the DNA lesions caused by these cytotoxic therapies (9,13,16,17). In addition to impairing singlestrand break (SSB) repair, the anticancer effects of PARP inhibitors have recently also been attributed to their ability to trap PARP-DNA complexes, thereby generating cytotoxic lesions (18).…”

Systematic review of en bloc resection in the management of Ewing’s Sarcoma of the mobile spine with respect to local control and disease free survival

“…In the United States, 200 cases are diagnosed annually, 14 of which <30 involve the mobile spine, 15 as only 5% of ES affects the mobile spine. 2 Continual advancement of systemic therapy, such as the recent discovery of PARP inhibitor efficacy, 16 will maintain CT as the most significant factor for improving survival. 3 Additionally, patients who undergo surgery are also thought to demonstrate improved survival.…”

“…Prognosis of ES is significantly influenced by the use of CT. 16,[25][26][27][28][29][30] Included papers in this review reported differing CT regimens, reflecting changes in CT use in ES. There are many confounding factors such as age, timing of surgery, neurological status, presence of metastases, and response to CT that could not be factored into the analysis.…”