Servicio de Oncología Médica, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA), Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.
Flow Cytometry Core Facility, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA), Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.
Sci Rep. 2017 Nov 30;7(1):16661. doi: 10.1038/s41598-017-17009-6.
Lung cancer remains the leading cause of cancer-related death worldwide, with one-third diagnosed with locally advanced (stage III) disease. Preoperative induction chemo-radiotherapy is key for the treatment of these patients, however conventional cisplatin based approaches has apparently reached a plateau of effectiveness. In the search for new therapies, the targeting of tumor metabolism is revealed as an interesting option to improve the patient's responses. Here we describe the importance of PGC-1alpha and GAPDH/MT-CO1 ratio levels as surrogates of the Warburg effect from a series of 28 stage III NSCLC patients, on PFS, OS and PET uptake. Moreover, our results show a great variability between tumors of different individuals, ranging from very glycolytic to more OXPHOS-dependent tumors, which compromises the success of therapies directed to metabolism. In this sense, using 3 different cell lines, we describe the relevance of Warburg effect on the response to metabolism-targeted therapies. Specifically, we show that the inhibitory effect of metformin on cell viability depends on cell's dependence on the OXPHOS system. The results on cell lines, together with the results of PGC-1alpha and GAPDH/MT-CO1 as biomarkers on patient's biopsies, would point out what type of patients would benefit more from the use of these drugs.
肺癌仍然是全球癌症相关死亡的主要原因，其中三分之一的患者被诊断为局部晚期（III 期）疾病。术前诱导化疗放疗是治疗这些患者的关键，但基于常规顺铂的方法显然已经达到了有效性的瓶颈。在寻找新的治疗方法时，靶向肿瘤代谢被证明是提高患者反应的一个有趣选择。在这里，我们描述了来自 28 名 III 期 NSCLC 患者的一系列研究中，PGC-1alpha 和 GAPDH/MT-CO1 比值水平作为瓦博格效应的替代物，对 PFS、OS 和 PET 摄取的重要性。此外，我们的结果显示，不同个体的肿瘤之间存在很大的变异性，从非常糖酵解到更依赖 OXPHOS 的肿瘤，这影响了针对代谢的治疗的成功。在这方面，我们使用 3 种不同的细胞系，描述了瓦博格效应对代谢靶向治疗反应的相关性。具体来说，我们表明二甲双胍对细胞活力的抑制作用取决于细胞对 OXPHOS 系统的依赖程度。细胞系的结果，以及患者活检中 PGC-1alpha 和 GAPDH/MT-CO1 作为生物标志物的结果，将指出哪种类型的患者将从这些药物的使用中获益更多。
