Probing the Metabolome in DIPG
Background
For this project, I will work with a new post-doctoral fellow in the Bindra Laboratory, Dr. Ranjith Menon, on an exciting project which is focused on understanding the metabolic profiles of diffuse intrinsic pontine glioma (DIPG) tumor cells. DIPG is a devastating childhood cancer with limited treatment options. Recent DIPG studies have revealed that ~80% of these tumors harbor activating mutations in key histone genes, such as histone H3. In parallel, emerging evidence suggests that metabolic and epigenetic processes are intricately linked in cancer. The Bindra laboratory and other groups have shown that tumor-associated metabolic changes induce vulnerabilities that can be targeted therapeutically. For example, Bindra and colleagues recently demonstrated that IDH1/2 mutations suppress homologous recombination (HR) and confer exquisite PARP inhibitor sensitivity. This work recently was published in Science Translational Medicine.
Project Goal
In this study, I will be involved in a project which will test the hypothesis that DIPG H3 K27M mutations induce metabolic defects, which can be exploited for a therapeutic gain. We will perform a comprehensive, targeted metabolomics profiling study to identify unique differences between H3 K27M mutant and wild-type cells. We will perform our initial studies in both neural progenitor cells and immortalized astrocyte cell lines engineered to express H3 K27M mutant proteins and we will confirm our results in patient-derived DIPG cells in vitro. Hits will then be validated using several unique in-vivo models, many of which were recently developed in the Bindra laboratory. These studies have the potential to create the first large scale model of DIPG metabolism and may lead to the discovery of novel druggable targets.
Mentored by Dr. Ranjit Bindra
Yale University, New Haven, CT
