Post-doctoral Fellowship Grant Awarded to Eshini Panditharatna

DIPG is a highly complex type of brain tumor, comprised of altered genetic and epigenetic patterns. Epigenetics dictate the timing, and expression of genes in human cells. As an analogy, in a piano score, DNA is similar to musical notes of the melody, and epigenetics is similar to the articulations, which dictates how the musical notes should be played. About 70-80% of DIPG tumors harbor a mutation in an epigenetic gene leading to dysregulation of normal epigenetic patterns. To improve the understanding of this dysregulation in DIPG, we conducted a gene knock-out experiment of more than 1,000 genes involved in epigenetics and cancer. Our goal was to identify the ‘Achilles heel’ of DIPG. We successfully identified a shortlist of 50 genes, which are essential for the survival of DIPG cancer cells. Among these 50 genes, top hits include five major epigenetic classes.

We are now proposing to genetically delete, and chemically target these five epigenetic classes and assess for DIPG cell death or differentiation into normal types of brain cells. Our goal is to understand the role of these specific epigenetic vulnerabilities in advancing DIPG biology, and to identify a novel combination of epigenetic targeted therapy to treat children diagnosed with DIPG. Through our proposed studies, we will also discover potential radiosensitizing epigenetic therapies, and novel avenues of differentiation therapy for treating this devastating disease.