Tumors, oncogenes, tumor suppressors, epigenetics , tumor stem cell markers and cell surface proteins
Pediatric brain tumors, DIPG , tumor associated with mutation in the histones
University of Colorado, Anschutz Medical Campus, Research buildings
To study the effect of inhibition of epigenetic genes that gives growth advantage to pediatric brain tumors specifically DIPG tumors
Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brain stem tumor that is essentially fatal. Curative surgery is not possible, radiation (IR) therapy provides only temporary relief, and chemotherapy is not effective. Recent studies have shown that a somatic p.Lys27Met substitution in histone 3.3 (H3.3K27M mutation) occurs in more than 80% of patients with DIPG and is associated with poor survival. While these studies give crucial insight into driver mutations they have not yet resulted in new therapeutic options. Thus, there is a critical need to identify and validate more effective, biologically based therapies to target DIPG. The mechanism by which the H3K27M mutation drives DIPG tumorigenesis is poorly understood. We hypothesize that other key epigenetic regulators are required to provide DIPG cells with a survival advantage in the presence of the H3K27M mutation. However, it is unclear which components of the epigenetic machinery are critical for DIPG cell growth and survival. To address this gap in knowledge we performed a functional genomic screen targeting 408 epigenetic/chromatin-associated molecules and a drug screen targeting those epigenetic genes. We identified 10 unique epigenetic genes that could be responsible for DIPG tumorigenesis and that are common in the complimentary screens performed. This study will be carried out by knockdown of each of these genes and determine the growth inhibition in multiple DIPG cell lines and in DIPG patient derived cells. Our major goal is to validate these genes and identify the most crucial target(s) that plays a key role in DIPG tumor growth by performing several biological assays and by RNA/DNA sequencing.