Drivers of metabolic plasticity promote radiation resistance in glioblastoma multiforme

摘要 放射治疗（RT）是一种非常有效的治疗方式，以改善局部控制 和总生存率的关系。然而，多形性胶质母细胞瘤（GBM） 显示出显著的抗辐射性虽然，术后RT（总剂量为60 Gy， 2Gy分次）是唯一增加GBM总生存率的治疗方式 患者中，GBM普遍复发且致命。因此，对RT的抗性是一个主要的 导致治疗失败。克服这些肿瘤的辐射抗性是一个 放射肿瘤学的主要剩余前沿领域，如果解决， 显著改善这种疾病的治疗效果。在众多因素中 已经提出，GBM代谢及其在产生抗性中的作用， 氧化应激，如在RT是一个有前途的治疗角度，我们将利用 在这个提议中。具体来说，我们有证据表明，辐射GBM细胞重新编程他们的细胞。 代谢向抗氧化剂途径，通过葡萄糖通过NADPH- 产生戊糖磷酸途径（PPP）。这种代谢重编程在 RT部分由糖酵解酶PKM 2介导，部分由转录调节。 因子NRF 2。PKM 2的氧化应激依赖性失活或NRF 2的活化， 两者都导致糖酵解中间体重新进入PPP。另外我们有 这表明PKM 2是NRF 2的靶点。因此，我们假设PKM 2和NRF 2 协同驱动辐射GBM细胞中的抗氧化代谢反应， 促进对RT的抗性。重要的是PKM 2在细胞中过表达， GBM肿瘤，而正常脑组织仅表达PKM 1。小分子 PKM 2的活化剂是可获得的，其加剧氧化应激并具有抗肿瘤活性。 活性，尽管它们尚未在GBM或RT中进行测试。 血脑屏障使它们适合于与RT组合以敏化GBM 肿瘤的因此，还提出干扰NRF 2-PKM 2-代谢 轴将限制抗氧化剂，促生存代谢重编程诱导 放射线和提高RT在人和小鼠GBM模型中的效果。

ABSTRACT Radiation therapy (RT) is a very effective treatment modality for improving local control and overall survival for many cancer types. However, glioblastoma multiforme (GBM) displays remarkable radioresistance. Although, post-surgical RT (total dose of 60Gy in 2Gy fractions) is the only treatment modality that increases overall survival for GBM patients, GBM universally recurs and is fatal. Resistance to RT is therefore a major contributor to treatment failure. Overcoming radiation resistance of these tumors is one of the major remaining frontiers in Radiation Oncology that, if resolved, could dramatically improve outcomes in this disease. Amongst the many contributing factors that have been proposed, GBM metabolism and its role in generating resistance to oxidative stress, such as during RT is a promising therapeutic angle that we will exploit in this proposal. Specifically, we have evidence that irradiated GBM cells reprogram their metabolism towards antioxidant pathways, by funneling glucose through the NADPH- generating pentose phosphate pathway (PPP). Such metabolic reprogramming during RT is mediated in part by the glycolytic enzyme PKM2 and in part by the transcription factor NRF2. Oxidative stress-dependent inactivation of PKM2 or activation of NRF2, both result in rerouting of glycolytic intermediates into the PPP. In addition, we have evidence that PKM2 is a NRF2 target. Therefore, we hypothesize that PKM2 and NRF2 cooperate in driving an antioxidant metabolic response in irradiated GBM cells that promotes resistance to RT. Of importance is the fact that PKM2 is overexpressed in GBM tumors, while normal brain tissue only expresses PKM1. Also, small molecule activators of PKM2 are available that exacerbate oxidative stress and have anti-tumor activity, although they have not been tested in GBM or with RT. These activators cross the blood brain barrier making them suitable for combining with RT to sensitize GBM tumors. Therefore, it is also proposed that interfering with the NRF2-PKM2-metabolism axis would limit the antioxidant, pro-survival metabolic reprogramming induced by radiation and improve the effect of RT in human and mouse models of GBM.