Our understanding of molecular pathogenesis of cancer has increased over the years and as a result personalized treatments became available. More recently pharmaceutics leading to changes in epigenetic landscape gained attention as a promising targeted treatment, mostly to support other cancer therapies. Although epigenetic alterations are effective in evaluation of disease risk, progression or clinical response, a precise correspondence between epigenetic treatment and chromatin response is not established for majority of pharmaceutics applied. Pediatric high-grade gliomas (pHGG) are amongst the most challenging cancers to treat with 5-year survival rates of approximately 28%, and in some specific cases such as diffuse midline glioma, only 2% . Importantly, pediatric tumors often accumulate mutations in epigenetic pathways, most commonly in histone H3, leading to global alterations in the epigenetic landscape of the chromatin. We hypothesize that elucidating molecular mechanisms evoked by the epigenetic treatment, i.e. changes in chromatin activity, will provide a key data for making progress in tumor research and targeted therapies in pHGG.
What are the goals of this project?
1) to revel chromatin accessibility and nucleosomal occupancy alterations in pediatric brain cancer cells
resulting from epigenetic treatment,
2) to identify chromatin alterations characteristic for particular treatments (e.g. expression of histone
variants, changes in post-translational modifications of histones)
3) to indicate mechanisms taking part in the treatment response.
Why the CBTN request is important to this project?
The collection of cell lines at the CBTN will be invaluable to globally investigate the epigenetic alterations of chromatin in response to epigenetic drugs. We are particularly interested to include in our study the pediatric cell lines with wt histone H3 as well as with the common mutations such as K27M or G34R, to help us to understand the role of histone mutations both in treatment and in chromatin accessibility. In addition, we are very much interested to use the cell lines derived from patients (early passages) to test the response to drugs and corresponding chromatin accessibility profiles, and the CBTNB pediatric cell line collection will be perfect for our aim.
The main goal of this project is to provide a characterization of epigenetic changes involved in the response to particular treatments in pediatric brain cancer cells, and form a framework for evaluating changes in chromatin accessibility for other stimuli. Direct analysis of the chromatin landscape in primary cultures of pediatric cancer cells will provide insights into epigenetic regulatory networks and profiles of chromatin physical properties associated with the response to the epigenetic treatment. Our project will constitute a novel approach, never before applied to study mechanisms of response to cancer treatment. Our results will provide new avenues to shape potential of cell responses, and better understand mechanisms standing behind success of combined therapies for pediatric HGGs.
High-grade glioma/astrocytoma (WHO grade III/IV)
High-grade Gliomas (HGG) in children nearly always result in a dismal prognosis. Although novel therapeutic approaches are currently in development, preclinical testing has been limited, due to a lack of pediatric specific HGG preclinical models. These models are needed to help test the effective