PARP inhibitor combinations with high-dose vitamin C in the treatment of Ewing sarcoma: two case reports and mechanistic overview.

Ewing's sarcoma (ES) is a bone and soft tissue tumor that mainly occurs at a young age. The underlying cause of Ewing's sarcoma is the formation of fusion proteins between FET family genes and ETS family genes. Tumors with FET/ETS fusion genes can have defects in the DNA damage response and are sensitive to PARP inhibitors (PARPi). However, several studies have shown that PARPi alone is not sufficient to induce a meaningful antitumor response and that combinations of DNA-damaging agents with PARPi are required to achieve efficacy. Accordingly, preclinical studies have reported dramatic responses to PARPi treatment in combination with DNA-damaging agents such as temozolomide or irinotecan. Similarly, it has been previously reported that by generating reactive oxygen species, high-dose intravenous vitamin C (IVC) can induce DNA damage. This suggests that the combination of IVC with PARPi may increase genotoxic stress and enhance the antitumor response. In addition, unlike chemotherapeutic agents, IVC induces DNA damage selectively in cancer cells, and the side effects are significantly milder than those of chemotherapy. As ETS fusion-positive ES is deficient in faithful DNA repair, partly due to the interaction between ETS fusion products and PARP1, a PARPi plus IVC seems to be a logical and effective combination for the treatment of ETS fusion-positive ES. This paper reports significant responses to IVC (1-1.5 g/kg) in combination with PARPi (olaparib 300 mg BID or talazoparib 1 mg/day) in two patients with metastatic Ewing's sarcoma. The observations highlight an unmet therapeutic need for patients with advanced metastatic ES. The combination of PARPi with a selective DNA-damaging agent was effective in these cases. This case experience suggests that IVC may be incorporated into PARPi-based therapeutic strategies. Further studies are needed to confirm the efficacy of this combination in the treatment of Ewing sarcoma with ETS fusions.