[Functional genomics of Ewing sarcoma]. / Funktionelle Genomik des Ewing­Sarkoms.

Ewing sarcoma is a highly aggressive bone or soft-tissue tumor mostly occurring in children and adolescents. Conventional multi-modal therapies are associated with considerable acute and chronic toxicity. Thus, more effective and in particular less toxic therapeutic strategies are urgently required. Despite the fact that Ewing sarcoma is characterized by specific EWSR1-ETS gene fusions, the resulting fusion oncoproteins are not suitable for targeted therapy due to their low immunogenicity and the ubiquitous expression of their constituents. However, functional genomics revealed several EWSR1-ETS target genes, which are only minimally expressed in normal tissues, and which could serve as surrogate-targets for (immuno-)therapeutic approaches. Moreover, functional genomic analyses yielded first mechanistic explanations for the relatively high incidence of Ewing sarcoma in Europeans, and first studies are exploring the value of circulating free DNA and/or exosomal mRNA of EWSR1-ETS fusion oncogenes as minimal-residual-disease markers in Ewing sarcoma. This review summarizes key contributions to these aspects and gives a perspective on their medical relevance.

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.

Combining vitamin C with PARP inhibitors for Ewing sarcoma treatment: mechanistic insights and 2 case studies Ewing's sarcoma is a type of bone and soft tissue tumor that commonly affects young people and it is often resistant to conventional therapy. In this study, clinical cancer scientists and oncologists investigated a new approach to treating this cancer by combining high-dose vitamin C with PARP inhibitors. High-dose vitamin C can damage the DNA of cancer cells and PARP inhibitors block the damaged DNA sites so they can't be repaired and eventually this leads to cancer cells dying. The researchers found that when these two treatments were used together, there were significant improvements in two patients with advanced Ewing's sarcoma. Importantly, the combination led to fewer side effects compared to standard chemotherapy, suggesting it might be a more tolerable treatment option. These findings suggest that combining high-dose intravenous vitamin C with PARP inhibitors could be a promising treatment for Ewing's sarcoma. More research is needed to confirm these results, but this approach shows potential for helping patients with advanced forms of this type of cancer. This is the first clinical report demonstrating the benefits of using high-dose vitamin C with PARP inhibitors and the study emphasizes the importance of exploring more treatment options for this aggressive type of cancer and suggests that further investigations into this combined approach could lead to more effective and tolerable treatments for Ewing's sarcoma.

Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation.

Ewing sarcoma (EwS) is characterized by EWSR1-ETS fusion transcription factors converting polymorphic GGAA microsatellites (mSats) into potent neo-enhancers. Although the paucity of additional mutations makes EwS a genuine model to study principles of cooperation between dominant fusion oncogenes and neo-enhancers, this is impeded by the limited number of well-characterized models. Here we present the Ewing Sarcoma Cell Line Atlas (ESCLA), comprising whole-genome, DNA methylation, transcriptome, proteome, and chromatin immunoprecipitation sequencing (ChIP-seq) data of 18 cell lines with inducible EWSR1-ETS knockdown. The ESCLA shows hundreds of EWSR1-ETS-targets, the nature of EWSR1-ETS-preferred GGAA mSats, and putative indirect modes of EWSR1-ETS-mediated gene regulation, converging in the duality of a specific but plastic EwS signature. We identify heterogeneously regulated EWSR1-ETS-targets as potential prognostic EwS biomarkers. Our freely available ESCLA (http://r2platform.com/escla/) is a rich resource for EwS research and highlights the power of comprehensive datasets to unravel principles of heterogeneous gene regulation by chimeric transcription factors.