Post-doctoral Fellowship Grant Awarded to Jamie Anastas

Scientists have identified driver mutations in genes encoding proteins called histones in most DIPG tumors.
Histones are abundant proteins that organize long DNA strands into a compact structure called “chromatin.”
Hundreds of factors cooperate to regulate chromatin in order to turn genes “on” or “off,” resulting in changes in
tumor cell behaviors like growth, invasion, and drug resistance. I screened ~1300 chromatin regulators to
identify factors that are required for DIPG proliferation and survival. These screens were a success and I’ve
identified multiple candidates that are required for the growth of DIPGs, but not normal cells. The overall goals
of my research are to determine the functional consequences of inhibiting these candidate genes in DIPG and
to learn how they regulate DIPG biology on a mechanistic level. Since my initial screens involved cells grown in
a dish, I will first test whether my top candidates are required for tumor growth in mouse brains. My data
suggests that inhibiting certain chromatin regulators causes DIPG cells to stop dividing and differentiate, or
behave more like normal brain cells. I will determine whether my candidate chromatin regulators similarly
regulate the proliferation and differentiation of DIPG cells, or if they induce other responses like cell death.
Finally, I will investigate mechanisms underlying DIPG dependencies on chromatin regulators by identifying
their molecular targets and determining how they regulate DIPG chromatin on a biochemical level. This
approach of targeting previously unknown DIPG chromatin dependencies is distinct from a majority of ongoing
studies focused on new applications of old drugs. It is possible that these existing drugs simply won’t work for
DIPG treatment. If successful, my studies will identify and characterize novel mechanisms governing DIPG
tumorigenesis, which will be an instrumental step towards the development of chromatin-targeted therapies
that may succeed where other treatment strategies have failed.