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Dr. Pollack’s group has extended their studies that define the mechanisms underlying resistance in childhood and adult malignant gliomas. They have expanded the repertoire of “drug-resistance” tumor model systems, paired with treatment naïve counterparts. The group has leveraged this unique resource to identify the NAD metabolic pathway as a key intermediate through which multiple cell lines achieve treatment resistance. Using RNA sequencing studies and pathway analysis, Dr. Pollack and his group have identified several common molecular drivers of this process, such as QPRT and NMNAT2. Gene set enrichment analysis has demonstrated that these mediators hijack glycolytic signaling. Metabolomic analysis of downstream signaling pathway components have shown an involvement of both glycolytic intermediates and mitochondrial energy metabolites that are amenable to therapeutic intervention. These observations have provided a basis for pharmacological and RNA interference-based strategies for reversing resistance as well as metabolic manipulations that may provide novel approaches for promoting tumor cell killing. Dr. Pollack’s group has demonstrated dramatic enhancement in survival with treatment in one orthotopic xenograft model and are planning studies using other models and dietary modulation, which may open up several novel strategies for clinical therapies.
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