Yin Wang, Ph.D.
First-year Children’s National, DC; University of Maryland, Baltimore
Two-year study, second year
Dr. Wang’s group has made significant progress for their project, “A Novel Mechanism and Immediately-Translatable Targeted-Therapy for Group 3 Medulloblastoma”. Their completed studies have demonstrated that HIF1α is a driver for infant Group 3 medulloblastoma (G3MB) by reciprocal positive regulation with MYC. They found that HIF1α enhances MYC expression through transcriptional and post-transcriptional mechanisms. In turn, MYC enhances HIF1a stability via inhibiting the E3 ligase VHL, which otherwise targets HIF1a for proteasome-mediated degradation. Thus, targeting HIF1α with liposomal echinomycin, an HIF1α specific inhibitor, efficiently dampens the oncogenic drivers, HIF1α and MYC, thereby effectively restraining primary G3MB growth and significantly extending the survival of mice xenografted with primary G3MB. Dr. Wang’s group is currently conducting studies to demonstrate the preclinical efficacy of liposomal echinomycin in G3MB mouse models. They have analyzed the dose response of PDX-F211, Icb-1299, and Icb-1459 primary cells to liposomal echinomycin in vitro and in vivo, and found that these cells are very sensitive to the drug. Furthermore, they are optimizing the liposomal formulation to include targeting ligand for selective uptake by brain tumor cells and thus maximize therapeutic index for pediatric therapeutic applications in infantile G3MB. They have tested the improved brain tumor-specific liposomal echinomycin in mice bearing PDX-F211 xenografts and found that the new formulation further increased survival rates compared to the prior formulation.