Mack Elisabeth, Rau Christian, Otet Cornelia, Schäfer Jonas Aaron, Brendel Cornelia, Grass Albert, Bredow Peer, Hohl Christian, Denkert Carsten, Willeke Frank, Neubauer Andreas
Dept. Internal Medicine, Hematology, Oncology, Immunology, Philipps University Marburg, and UKGM, Marburg, Baldingerstrasse 1, 35033, Marburg, Germany; Dept. Oncology, Marienkrankenhaus Siegen, Kampenstraße 51, 57072, Siegen, Germany.
Dept. Oncology, Marienkrankenhaus Siegen, Kampenstraße 51, 57072, Siegen, Germany.
Redox Biol. 2025 Jun 14;85:103726. doi: 10.1016/j.redox.2025.103726.
KRAS mutations are frequently observed in human cancer and are associated with proliferation, therapy-resistance and worse outcome. Regrettably, only a fraction of possible mutations is druggable. Therefore, a tailored and possibly cost-effective method to overcome this issue is urgently needed. Recently, Bodeker et al. presented a randomized phase II trial investigating whether high-dose vitamin C (ascorbate) improved overall survival in metastatic pancreatic cancer (Bodeker et al., Redox Biol 2024). This may be due to the high frequency of KRAS mutations in pancreatic cancer (>90 %), as, in the case of oncogenic RAS, high-dose vitamin C becomes synthetic lethal when added to chemotherapy, as previously shown by the work of Cantley and coworkers (Yun et al., Science, 2015) It is unclear, however, if this observation holds true also for rare KRAS mutations. Recently we treated a 43 year old male patient with metastatic duodenal cancer and an atypical KRAS mutation A59T using FOLFOX-chemotherapy with high-dose vitamin C as second line therapy. The tumor had progressed after first line immune checkpoint therapy as the tumor presented with microsatellite instability. Restaging after 8 cycles of FOLFOX + high-dose vitamin C therapy revealed regression of the tumor mass and extensive tumor necrosis. Thus, our personalized experimental approach yielded in a greater clinical benefit for the patient than the previous standard therapy, particularly a PFS-2/PFS-1 ratio of >2. Obviously we do not know whether this response could have also been observed if chemotherapy was given w/o high-dose vitamin C. As up to now two randomized clinical trials showed a beneficial effect of the addition of high-dose vitamin C (pancreatic cancer: Bodeker et al., colorectal cancer: Vitality trial), and, in the case of Vitality, the benefit was restricted to KRAS mutated tumors only, more clinical trials addressing this topic are needed. Therefore, we thank Bodeker et al. for contributing these important data.
KRAS突变在人类癌症中经常被观察到，并且与增殖、治疗抗性和更差的预后相关。遗憾的是，只有一小部分可能的突变是可靶向治疗的。因此，迫切需要一种定制的且可能具有成本效益的方法来克服这个问题。最近，博德克等人开展了一项随机II期试验，研究高剂量维生素C（抗坏血酸）是否能改善转移性胰腺癌的总生存期（博德克等人，《氧化还原生物学》，2024年）。这可能是由于胰腺癌中KRAS突变的频率很高（>90%），因为就致癌性RAS而言，如坎特利及其同事之前的研究所示（尹等人，《科学》，2015年），当高剂量维生素C与化疗联合使用时会产生合成致死效应。然而，尚不清楚这种观察结果是否也适用于罕见的KRAS突变。最近，我们对一名43岁患有转移性十二指肠癌且带有非典型KRAS突变A59T的男性患者，使用含高剂量维生素C的FOLFOX化疗作为二线治疗。一线免疫检查点治疗后肿瘤进展，因为肿瘤表现出微卫星不稳定性。8个周期的FOLFOX + 高剂量维生素C治疗后的重新分期显示肿瘤肿块缩小且广泛肿瘤坏死。因此，我们的个性化实验方法为患者带来了比先前标准治疗更大的临床益处，特别是无进展生存期2/无进展生存期1的比值>2。显然，我们不知道如果不使用高剂量维生素C进行化疗是否也能观察到这种反应。由于到目前为止两项随机临床试验显示添加高剂量维生素C有有益效果（胰腺癌：博德克等人；结直肠癌：活力试验），而且在活力试验中，益处仅局限于KRAS突变的肿瘤，因此需要更多针对这个主题的临床试验。所以，我们感谢博德克等人提供这些重要数据。
