Targeting Metabolism as a Therapeutic Approach for High-Risk MYCN-Driven Neuroblastoma
In 30-percent of neuroblastoma cases aberrant activity of the MYCN-gene is present. Current therapies for high-risk MYCN-driven neuroblastoma are ineffective, and only 40% of children with disease can achieve long-term event-free survival. These realities underscore the urgent need to discover novel therapeutic strategies that are more effective in combating neuroblastoma.
Because cancer cells reprogram their cellular metabolism in order to meet the increased energy and nutrient requirements of uncontrolled cell division, and metabolic reprograming represents a fundamental difference between normal and cancer cells. Recent experimental and pre-clinical evidence provide encouraging perspectives to target this metabolic difference in treating cancers driven by C-MYC, a close relative of MYCN. My previous studies on T-cell acute lymphoblastic leukemia identified a key metabolic enzyme, dihydrolipoamide S-succinyltransferase (DLST), whose partial inactivation significantly inhibits c-MYC-driven leukemia development in zebrafish yet minimally affects fish development. I have since extended this research to include high-risk MYCN-driven neuroblastoma, and found that DLST is also important for neuroblastoma pathogenesis.
The goals of this proposed research are a) to test if targeting DLST alone or in combination with another metabolic enzyme (isocitrate dehydrogenase 2) can suppress neuroblastoma development and b) to understand how DLST contributes to MYCN-driven neuroblastoma. My research will determine viability of targeting DLST, and will also generate information to guide metabolism-based therapy as a new strategy to treat high-risk neuroblastoma.
"I am grateful and honored to receive a Young Investigator Grant from the Alex Lemonade Stand Foundation. Your support is critical in enabling young scientists to pursue research careers dedicated improving our understanding of childhood cancer and for developing new cures." - Nicole Anderson, PhD