Jamie Anastas, PhD – Young Investigator – Pediatric High-Grade Glioma

My current research focus is on pediatric high-grade glioma (pHGG), a class of rare but aggressive brain tumors frequently harboring mutations in genes encoding histones including H3K27M substitutions in diffuse intrinsic pontine glioma (DIPG) and H3G34R/V mutations in hemispheric glioblastomas. This research addresses a critical, unmet clinical need as there are no effective therapies for these tumors leading to a two-year survival for DIPG patients of <10%. My ongoing research centers on the hypothesis that aberrant chromatin regulation gives rise to clinically relevant cancer phenotypes including the induction of tumor-initiating cancer stem cells (CSCs) and drug resistant subpopulations. As an independent investigator, my goal is to establish a research program aimed at understanding if and how chromatin dysregulation contributes to CSC maintenance and the development of therapeutic resistance on a mechanistic level, and at leveraging this knowledge to develop new therapies.

This research will address three primary questions: (1) Which chromatin pathways are necessary for pHGG growth and what are the molecular mechanisms driving these dependencies?; (2) How do chromatin regulators contribute to the development of therapeutic resistance in pHGG and can we rationally target the epigenome in combination with other drugs to achieve lasting disease control?; (3) More generally, how are the activities of multiple signal transduction pathways stimulated by WNTs and other signals integrated at the level of chromatin in order to drive complex phenotypes like the maintenance of cancer stem cells?

Although my work will initially focus on understanding and identifying novel strategies for targeting epigenetic pathways in pediatric gliomas harboring histone mutations, these studies will also prepare me to apply similar research methods to understand molecular mechanisms driving a variety of pediatric cancers.