Neuroblastoma is a very aggressive pediatric cancer, which accounts for 15% of all pediatric cancer deaths and has an overall survival of less than 45%. Current front-line therapies have reached maximum tolerated toxicity, and novel approaches are desperately needed. Importantly, patients with a specific genetic aberration, the amplification of the oncogene MYCN, relapse much earlier and develop resistance to current therapy modalities. Once relapsed, the overall survival for these patients is less than 20%. Cell metabolism, or the way in which cells take up and process nutrients such as sugars, amino acids, and lipids, is a key aspect of tumor cell biology. Cancer cells adopt distinct meta...

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Neuroblastoma is a very aggressive pediatric cancer, which accounts for 15% of all pediatric cancer deaths and has an overall survival of less than 45%. Current front-line therapies have reached maximum tolerated toxicity, and novel approaches are desperately needed. Importantly, patients with a specific genetic aberration, the amplification of the oncogene MYCN, relapse much earlier and develop resistance to current therapy modalities. Once relapsed, the overall survival for these patients is less than 20%. Cell metabolism, or the way in which cells take up and process nutrients such as sugars, amino acids, and lipids, is a key aspect of tumor cell biology. Cancer cells adopt distinct metabolic changes to sustain their biosynthetic growth demands, including the rewiring of fatty acid metabolism. We have recently discovered in the laboratory that the "non-druggable" oncogene MYCN causes neuroblastoma to become more reliant on fatty acid metabolism in order to support its aggressive growth. Moreover, MYCN represses the expression of BMAL1, a master circadian factor, which regulates tumor-specific and time-specific changes in fatty acid metabolism, dictating tumor progression and response to therapy. In this proposal, we aim to elucidate the interactions between MYCN oncogenesis, tumor metabolism, and response to therapy, and exploit them to develop novel therapeutic interventions for MYCN-amplified neuroblastomas. By boosting BMAL1 expression with novel drugs targeting the molecular clock and by dissecting the circadian and metabolic state of neuroblastoma tumors, we will understand when to best deliver conventional and metabolic therapies. Ultimately, this proposal will lead to the development of novel metabolic therapies for MYCN-amplified neuroblastomas and other tumor types that are driven by MYCN or c-MYC, which together are altered in at least 50% of cancers.

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