Project Summary
The overarching goal of this proposal is to define the interplay of epigenetics and developmental context in
driving pediatric high-grade gliomas (pHGG), universally lethal tumors defined by histone mutations, so as to
identify better targeted treatments. This work utilizes an innovative cerebral organoid-based model that allows
side-by-side comparison of oncohistone mutants and dynamic modulation of oncogene expression in a three-
dimensional human context. Leveraging this innovative model, Dr. Graham will use cutting-edge single cell
profiling techniques and preclinical glioma modeling to address unanswered questions that currently hamper
therapeutic development for these patients. In Aim 1, chromatin profiling and single cell RNA sequencing will
be used to investigate the distinct effects of two different oncohistones (H3.3K27M and H3.3G34V) during neural
development. In Aim 2, the timing and order of mutations will be manipulated to evaluate the impact of cellular
and mutational context on tumor phenotype. Finally, in Aim 3, orthogonal genetic “rescue” and pharmacologic
inhibition approaches will be used to interrogate the role of these mutations in tumor maintenance.
This work, as well as Dr. Graham's career goal, is well-aligned with the NINDS mission to seek basic
knowledge about the brain and to translate that knowledge into clinical impact. Through the proposed studies
and the accompanying career development plan, Dr. Graham will gain essential training in epigenetics,
bioinformatics and preclinical glioma studies, critical gaps in her current skillset. Dr. Graham is an Instructor of
Neuro-Oncology under the mentorship of Dr. Ingo Mellinghoff at Memorial Sloan Kettering Cancer Center
(MSK). Dr. Mellinghoff is a leader in translational glioma research with a strong track record of mentoring
trainees to independence. He and Dr. Graham have assembled an exceptional Advisory Committee with
expertise in chromatin biology, translational oncology, and bioinformatic analyses: Dr. Kristian Helin, Dr. Ross
Levine and Dr. Nicholas Socci. MSK provides an outstanding environment for cultivating budding careers in
biomedical research, with unparalleled resources, support, and opportunities for collaboration. Upon
completion of the proposed work, Dr. Graham will be ideally positioned and uniquely qualified for a career as
an independent investigator elucidating fundamental aspects of epigenetic regulation in neural lineage
commitment and applying her findings to address the unmet needs in the treatment of malignant glioma.