The Synergistic Effect Of Dichloroacetate And Low-dose Oncolytic Measles Virus To Glioblastoma

Targeting metabolism reprogramming merges as an efficient therapeutic strategy in cancer treatment. However, the metabolic heterogenecity within a single tumor lesion or among various cancers may lead to resistance to this therapeutic modality. Viral infection has been shown to alter cellular metabolism. We hypothesize that a modality firstly synchronizes or drives cancer cells to high-rate glycolysis followed by targeting metabolic flux may result in a more profound anti-tumor efficacy.In this study, we found that the attenuated measles virus vaccine strain (MV-Edm) could shift glioblastoma cells to a high-rate aerobic glycolytic adaption. Upon infection, glioma cells exhibited an increased glucose consumption, lactate production and ATP generation. When combined MV-Edm with an orphan drug dichloroacetate (DCA), an inhibitor of anaerobic glycolysis, a profound anti-tumor efficacy was observed both in vitro and in a subcutaneous glioma mouse model. We further confirmed that the synergistic effect was not caused by apoptosis, but by necrosis due to irreversible bioenergetic crisis.Moreover, we found that DCA functionally attenuated MAVS mediated anti-viral immune responses by reduction of mitochondria membrane potential and significantly promoted viral replication in glioma cells. Consequently, increased viral replication further exhausted bioenergetics leading to enhanced oncolysis. Out the other side, DCA blocks aerobic glycolytic adaption to MV-Edm to reduce the ATP production. So the combination of DCA and MV-Edm leaded to cellular ATP exhaustion at last. In summary, oncolytic MV-Edm shift cancer cells a high-rate aerobic glycolytic adaption.In parallel, DCA promoted viral replication and enhanced oncolyitic efficacy,thus cellular ATP consumption. DCA also blocked glycolysis to inhibit ATP production. So the combination of DCA and MV-Edm leaded to cellular ATP exhaustion and induced necrosis. As both MV-Edm and DCA have entered into cancer clinical studies, we provide in proof-of-principle a novel anti-tumor strategy which can be easily translated into treatment of cancer patients.