MYCN Reprograms Neuroblastoma Metabolism
Abstract
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. Tumors frequently have significant alterations, or undergo rewiring, in the specific types of nutrients they require and the way in which they use these nutrients. Certain genes are often associated with driving these critical changes in tumor cell metabolism, which in turn define their aggressive nature. We have recently discovered in the laboratory that the oncogene MYCN is capable of driving distinct metabolic changes that are associated with aggressive disease. In particular, this non-druggable oncogene causes neuroblastoma to become more reliant on lipid metabolism in order to support its aggressive growth. In this proposal, we aim to elucidate how MYCN alters lipid metabolism to promote tumor growth and drug resistance. We also aim to therapeutically target these metabolic features in order to block tumor progression and enhance the sensitivity of neuroblastoma to conventional treatment modalities. These studies will provide guidance for drug development efforts aimed at targeting the dependence of neuroblastoma on lipid metabolism. They will also enable us to identify novel metabolic vulnerabilities that will offer new avenues for treating this aggressive and deadly disease. Furthermore, our efforts have the potential to be applied to other tumor types that are driven by MYCN or its homologs, such as MYC, which together are amplified or altered in at least 50% of cancers. More broadly, we expect that the proposed research will also provide new insights into the regulation of energy metabolism and utilization of specific nutrients in cancer progression and drug-resistance. Ultimately, the possibility of developing more targeted and less toxic therapies is a key component to alleviate the hardship the young military families affected by this deadly disease have to endure.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910556
Entities
People
- Eveline Barbieri
Organizations
- Texas Children's Hospital
- United States Army