LIGHTING THE FIGHT AGAINST CHILDHOOD CANCER

Kate Amato Foundation Awarded Projects

Understanding the Role of MYCN-Driven FA Update to LIPID Metabolism and Tumor Growth to Identify a Targeted Approach for High-Risk MYCN-Amplified Neuroblastoma

Project Goal: Targeting this process (via FATP2 inhibition) may represent a novel and selective therapeutic approach for high-risk MYCN-amplified NBs.

Ling-Tao-Baylor-KAF-Grant-2019

Institution: Texas Children’s Cancer Center, Baylor College of Medicine

Researchers: Ling Tao, PhD

Year Awarded: 2019

Type of Childhood Cancer: High-Risk MYCN-Amplified Neuroblastoma

Project Description:

Metabolism is a fundamental cell activity. Tumors develop distinct metabolic patterns to promote growth and survival. These include activated uptake and biosynthesis of nutrients (proteins, sugars, and lipids) and enhanced bioenergetic pathways to fuel cell growth. The unique metabolic features of tumor cells provide opportunities for developing novel and targeted therapies. Neuroblastoma (NB) causes 15% of total childhood cancer death. MYCN is the major driver for NB oncogenesis, and almost half of high-risk patients harbor MYCN amplification. High MYCN expression confers multidrug resistance and strongly correlates with poor survival. Thus, strategies antagonizing MYCN functions need to be developed to improve NB survival. Our data suggest that MYCN activates lipid metabolism and energy production to promote tumor growth. This process requires fatty acids (FAs), which can be acquired through synthesis or direct uptake from microenvironment. We found that MYCN-driven tumors strongly depend on exogenous FAs for survival. Therefore, we hypothesize that MYCN drives FA transport to promote NB tumor growth. To test this hypothesis, we will alter FA uptake by interfering with the FA transporter FATP2 (a novel MYCN target) and determine its impact on lipid metabolism and cell survival. We will also test the anti-tumor activity of a small molecule inhibitor of FATP2 in multiple pre-clinical mouse models, including patient-derived xenograft model. Successful completion of the study will determine the importance of FA uptake in MYCN-driven oncogenesis. Importantly, targeting this process (via FATP2 inhibition) may represent a novel and selective therapeutic approach for high-risk MYCN-amplified NBs.

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