尤因肉瘤(ES)是一种骨和软组织肿瘤,主要发生在年轻时。尤因肉瘤的根本原因是FET家族基因和ETS家族基因之间融合蛋白的形成。具有FET/ETS融合基因的肿瘤可在DNA损伤应答中具有缺陷并且对PARP抑制剂(PARPi)敏感。然而,多项研究表明,单独PARPi不足以诱导有意义的抗肿瘤反应,需要将DNA损伤剂与PARPi联合使用才能取得疗效.因此,临床前研究报道,PARPi与DNA损伤药物如替莫唑胺或伊立替康联合治疗有显著反应.同样,以前有报道说,通过产生活性氧,大剂量静脉注射维生素C(IVC)可引起DNA损伤。这表明IVC与PARPi的组合可以增加基因毒性应激并增强抗肿瘤反应。此外,与化疗药物不同,IVC在癌细胞中选择性地诱导DNA损伤,副作用明显比化疗温和。由于ETS融合阳性ES缺乏忠实的DNA修复,部分由于ETS融合产物与PARP1之间的相互作用,PARPi+IVC似乎是治疗ETS融合阳性ES的合乎逻辑且有效的组合.本文报道了两名转移性尤文氏肉瘤患者对IVC(1-1.5g/kg)联合PARPi(奥拉帕利300mgBID或talazoparib1mg/天)的显着反应。观察结果强调了晚期转移性ES患者的治疗需求未得到满足。在这些情况下,PARPi与选择性DNA损伤剂的组合是有效的。该病例的经验表明,IVC可以纳入基于PARPi的治疗策略。需要进一步的研究来证实这种组合在ETS融合治疗尤文肉瘤中的疗效。
将维生素C与PARP抑制剂结合用于尤文肉瘤治疗:机制见解和2个案例研究尤文肉瘤是一种骨和软组织肿瘤,通常会影响年轻人,并且通常对常规治疗产生抗药性。在这项研究中,临床癌症科学家和肿瘤学家研究了一种通过将高剂量维生素C与PARP抑制剂联合治疗这种癌症的新方法.高剂量维生素C可以破坏癌细胞的DNA,而PARP抑制剂会阻断受损的DNA位点,因此无法修复,最终导致癌细胞死亡。研究人员发现,当这两种治疗方法一起使用时,2例晚期尤因肉瘤患者有显著改善.重要的是,与标准化疗相比,这种联合疗法的副作用更少,这表明这可能是一种更容易接受的治疗选择。这些发现表明,大剂量静脉注射维生素C与PARP抑制剂联合治疗尤文氏肉瘤可能是一种有希望的治疗方法。需要更多的研究来证实这些结果,但是这种方法显示出帮助晚期癌症患者的潜力。这是第一份临床报告,证明了使用高剂量维生素C与PARP抑制剂的益处,该研究强调了探索这种侵袭性癌症的更多治疗选择的重要性,并表明对这种联合方法的进一步研究可能会导致更有效和可耐受的治疗尤文氏肉瘤。
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.