To identify novel therapeutic targets of pediatric, we conducted an unbiased meta-analysis of gene signatures from multiple public datasets including the Cancer Genome Atlas (TCGA) Low-grade Glioblastoma. Our preliminary work identified a gene network centered on the FoxM1 transcription factor. FoxM1 is a master regulator of cell cycle and plays important roles in maintaining neural, progenitor, and GBM stem cell. FoxM1 has been shown to play roles in radioresistance, EMT, invasion and metastatsis in glioblastoma cells. It is emerging as a biomarker of poor prognosis and a potential therapeutic target in multiple cancers. It is involved with DNA repair, centromere and kinetochore assembly and is downstream of multiple signaling pathways including PI3K/Akt/Foxo, Nf-kB/Stat3, β -catenin/Wnt, HIF1a as well as metabolic/oxidative stress response. Given the central role of FoxM1 in proliferation, differentiation and cell death, its transcription must be tightly regulated throughout the development of a glioma cell. Our preliminary data suggests DNA Homologous Repair (HR) deficiency and TP53 loss underpin a large fraction of FoxM1-hyperactive pediatric glioblastoma and multiple other solid tumors. FoxM1 dysregulation in the absence of TP53 is likely catastrophic as it circumvents normal cellular protective mechanisms such as apoptosis and senescence while promoting genome instability and mutagenesis. The genetic cause and molecular players regulating FoxM1 transcription in glioblastoma is poorly understand currently.
What are the goals of this project?
To explore FoxM1 as a novel therapeutic target in glioblastoma, we propose to exploit the CBTN data to determine genetic factors inducing FoxM1 hyperactivation in pediatric cancers. We will apply a combination of computational analysis, high-throughput sequencing and biochemistry experiments.
The Children's Brain Tumor Network contributed to this project by providing access to the Pediatric Brain Tumor Atlas.
PI: Lihua Zou
Rintaro Hashizume, MD, PhD
Dr. Hashizume's primary research interests in understanding of the molecular mechanisms, that affect the aggressive/ invasive biological behavior of pediatric malignant glioma and would accordingly reveal potential therapeutic targets for glioma therapy.
Ann & Robert H. Lurie Children’s Hospital of Chicago