Post-doctoral Fellowship Grant Awarded to Brian Krug

Diffuse Intrinsic Pontine Gliomas (DIPG) display distinctive biological characteristics due to the type of
cells from which they arise and acquired genetic mutations, including the histone H3K27M mutation initiating
the disease. However, how DIPGs reprogram nutrient consumption and usage via metabolic pathways to sustain
their growth is not well understood. Using high-throughput profiling of metabolites from DIPG cell lines and
tumor tissue, we have uncovered a pattern of the H3K27M mutation transforming cells' behavior to elevate the
consumption and breakdown of branched chain amino acids (BCAAs); leucine, isoleucine and valine.
Importantly, we have also found that tumor cells and the oligodendrocyte lineage giving rise to tumors both
express the enzyme BCAT1, involved in breakdown of BCAAs. Our preliminary data suggests that DIPG cells
require BCAT1 to grow in cell culture. Numerous cancers depend on BCAT1, with several candidate mechanisms
being proposed. Our work aims to establish the reason why DIPG tumors depend on the metabolism of BCAAs,
using methods to track the nutrients they are converted into, and by investigating why DIPG cells fail to grow
when losing BCAT1 function. Second, we aim to test if there are therapeutic benefits for patients from reducing
the levels of BCAAs in the diet through tailoring food composition. These diets have previously been established
as safe and effective for treating specific metabolic disorders in children, and have shown that they can alter
behavior of leukemia cancer cells in mice. Our proposed work will drive understanding of how specific nutrients
are utilized by the developing brain cells at risk of DIPG formation, and potentially present a novel way to
eradicate DIPG growth and prolong survival of patients.