靶向神经胶质瘤有氧糖酵解的病毒溶瘤策略及机制研究

Targeting aerobic glycolysis （Warburg effect） and oncolytic virotherapy are both effective strategies against human malignant glioma and have entered several clinical trials. However, the metabolic heterogeneity of cancer cells and the anti-viral innate immunity constitute two major hurdles for antitumor efficacy. Our preliminary data showed that oncolytic measles viruses rapidly shift glioma cells into high-rate aerobic glycolytic adaptation. And we also found that the anti-viral innate immune response was significantly decreased when aerobic glycolysis was inhibited (e.g. by dichloroacetate) thus promoted viral replication within glioma cells. However, the mechanisms require further investigation. We then postulate a novel therapeutic strategy that may achieve profound antitumor effect against malignant glioma: first, to shift cancer cells to high-rate aerobic glycolysis by infection with oncolytic measles virus (metabolic synchronization), thus sensitizes cancer cells to therapeutic modality directed against aerobic glycolysis; second, to mitigate anti-viral innate immune response by inhibition of aerobic glycolysis, thus promotes viral replication and oncolysis, and moreover, blocked aerobic glycolysis decreases lactate generation induced by viral infection. In this study, we investigate the therapeutic efficiency of this strategy in glioma cells and in a glioma-bearing nude mouse model. Moreover, the crosstalk between Warburg effect and innate immunity, and its molecular mechanisms, will be intensively elucidated. The results are expected to provide an effective therapeutic modality against malignant glioma which can be readily translated into clinical studies.

靶向肿瘤有氧糖酵解（瓦堡效应）和溶瘤病毒都是治疗恶性神经胶质瘤有效的策略并已进入临床试验。但癌细胞存在的代谢异质性(如细胞对有氧糖酵解不同的依赖程度)和抗病毒固有免疫，是限制上述策略疗效的重要障碍。我们前期发现，溶瘤麻疹病毒能快速驱动胶质瘤细胞进入高有氧糖酵解状态；同时还发现，抑制有氧糖酵解（如二氯乙酸）能有效抑制细胞抗病毒固有免疫反应，促进溶瘤病毒瘤内复制（机制尚不清楚）。因此，我们提出一个新的治疗人恶性神经胶质瘤策略：通过溶瘤麻疹病毒上调肿瘤细胞有氧糖酵解(代谢同步化)，使肿瘤对靶向糖酵解的治疗敏感；同时利用靶向有氧糖酵解来抑制细胞抗病毒固有免疫，促进病毒复制和溶瘤，并能对抗溶瘤病毒导致的肿瘤微环境乳酸增高。本课题将在细胞水平和裸鼠胶质瘤模型中验证其疗效，并在细胞和分子水平阐明瓦堡效应与固有免疫间的对话及机制。结果将为治疗人类恶性胶质瘤提供一有效并适于临床转化的治疗策略。

靶向肿瘤有氧糖酵解（瓦堡效应）和溶瘤病毒都是治疗恶性肿瘤有效的策略并已进入临床试验。但实体肿瘤细胞存在的代谢异质性(如细胞对有氧糖酵解不同的依赖程度)和免疫负性调控，是限制上述策略疗效的重要障碍。本研究分为两个部分，第一部分研究了溶瘤麻疹病毒（MV）与靶向神经胶质瘤有氧糖酵解的策略及相关机制；第二部分研究溶瘤新城疫病毒（NDV）与靶向肝癌有氧糖酵解在溶瘤免疫中的作用。.研究结果发现，MV能快速驱动胶质瘤细胞进入高有氧糖酵解状态；抑制有氧糖酵解（如二氯乙酸，DCA）能有效抑制细胞抗病毒固有免疫反应，促进溶瘤病毒瘤内复制，最终导致胶质瘤细胞能量合成不足与过度消耗，引起细胞坏死性死亡从而增强MV-Edm溶瘤；小鼠活体实验证实，MV-Edm联合DCA能够显著抑制胶质瘤在小鼠体内的生长，并没有明显的毒副作用。本课题首次在细胞和分子水平阐述了瓦堡效应与固有免疫间的对话。.NDV能够诱导肝癌细胞进入有氧糖酵解依赖、诱导抗肿瘤免疫，但同时上调介导肿瘤免疫逃逸的分子如STAT3的活化、代谢酶IDO1；DCA能够有效抑制NDV诱导的有氧糖酵解、抑制NDV诱导的STAT3磷酸化并促进IDO1的降解；另外，DCA能够有效降低肿瘤微环境中的免疫抑制型细胞MDSC的水平，从而更有效地促进抗肿瘤免疫，在小鼠腹水瘤模型中， DCA联合NDV能够达到25%的完全缓解率。本研究为临床晚期肝癌患者提供了一个新的有效治疗策略。.本课题从靶向有氧糖酵解的角度，系统阐明了该策略对溶瘤病毒介导的肿瘤免疫治疗的重要影响，为今后溶瘤免疫治疗的临床应用，提供了一种能够转换的有效策略。