Glioblastoma is the most devastating form of brain cancer, and most glioblastoma tumors are resistant to conventional therapies. Females are less likely than males to develop the disease, and when they do, they have better outcomes. Previous work showed that these differences are due to cellular identity, specifically, distinct sex-specific cellular responses to chemotherapeutics and to mutations affecting tumor suppressor genes. Recently, cellular identity has been tightly linked to differences in the activity of super enhancers, roughly 300 regions in DNA that regulate the activity of genes in each cell.
This project will examine whether differences in super enhancer activity underlie male-versus-female cellular identity and contribute to the sex differences in thresholds for transformation (i.e., cancer rates) and outcomes (i.e., drug sensitivity).
· Enumerate sex differences in super enhancer activity and determine the effects on gene expression.
· Identify genes that contribute to sex differences in thresholds for malignant transformation.
· Map the gene regulatory network underlying sex differences in thresholds for transformation.
Potential impact on child health
Glioblastoma causes significant morbidity in infants. This approach is promising because novel targets identified through the study of sex differences are likely to both be effective and have fewer side effects, since modulation of these targets already happens in females.
Joshua Rubin, M.D., Ph.D. and Donald Conrad, Ph.D.