Targeting OGDH for Glioblastoma Therapy

Glioblastoma WHO IV (GBM) is the most common primary brain tumor with about 8500 cases diagnosed each year in the United States. Within a time frame of roughly one year almost all patients succumb to this detrimental disease despite treatment. Therefore, novel, ideally tumor specific approaches are necessary to combat these tumors. Tumor growth is ultimately determined by nutrients. We have shown before that lactate accumulates to a significant amount in GBMs and that lactate rescues a broad range of GBM cells from nutrient deprivation mediated cell death, which is dependent on the tricarboxylic acid (TCA) cycle. Through interrogation of genome wide pooled CRISPR library screens performed in GBM models, we unexpectedly found that OGDH (2- oxoglutarate dehydrogenase), a key enzyme of the TCA-cycle, is a critical driver gene for glioblastoma growth. Using a clinically validated OGDH inhibitor (CPI-613) we found that this drug extended animal survival. We will take these findings further and extend our research in the underlying mechanisms and will assess the overall hypothesis that the standard of care is enhanced by loss of function of OGDH, involving appropriate pharmacodynamics and pharmacokinetic analyses. The knowledge generated from this proposal has the potential for high-impact paradigm changing science, knowledge that will ultimately and hopefully at some point allow us to defeat this detrimental disease.