Grants and Contracts Details
Description
Abstract
The prognosis for children diagnosed with Diffuse Intrinsic Pontine Glioma has not
changed in nearly 50 years—children have no chance for survival because there are no
effective treatments for this cancer. DIPG is inoperable because it grows intertwined in the
brainstem, and DIPG always becomes resistant to the current standard of care, radiation
therapy. Although a key mutation in histone 3, H2(K27M) was recently identified in a majority of
DIPG, this has not translated to new therapeutic options as originally hoped. Our long-term goal
is to help develop new therapeutic approaches to treat DIPG using our expertise with zebrafish
cancer modeling. The objective of this proposal is to use zebrafish that we have engineered to
express H3(K27M) in glia to understand the effects of this mutation on DIPG progression and
and to identify FDA-approved drugs that can be repurposed to block these phenotypes. The
rationale for this project is that zebrafish models will fill critical gaps in our currently available
tools to study DIPG. Unlike mouse models, fluorescently tagged tumor cells can be easily
studied in the zebrafish brain from the earliest stages of tumor growth onwards to the
development of radiation resistance. Cross species comparisons between human and zebrafish
tumors can reveal critical proteins involved in tumor progression. Zebrafish are also an
inexpensive animal model for rapid and large-scale drug screens; unlike cultured cells, DIPG in
zebrafish grows in its native neural niche and under a blood-brain barrier, which can be more
informative for drug testing. The objectives of this proposal will be met with the following specific
aims: 1) Define the effects of H3(K27M) in DIPG onset and the acquisition of radio resistance
using a zebrafish expressing H3(K27M) in glia, and 2) Perform large scale drug screens in
zebrafish DIPG models to identify drugs that can revert DIPG phenotypes. Under the first aim,
zebrafish with H3(K27M) mutation in their glia will be assessed for DIPG onset and progression
both microscopically and histologically. Animals will also be irradiated to assess the effects of
H3(K27M) in radioresistance mechanisms. Samples will be harvested for transcriptomics and to
analyze the genome occupancy of H3(K27M) via chromatin immunoprecipitation sequencing. In
the second aim, we will utilize both the H3(K27M) zebrafish model and patient derived
xenografts in zebrafish for large scale screening of FDA-approved drugs to identify compounds
that eliminate DIPG and/or revert the radioresistance phenotype. This research is innovative
because it will develop and employ novel zebrafish models to define key events DIPG onset,
which cannot be done in current mouse and cell culture models, and test the efficacy of large
panels of drugs in targeting DIPG in its native neural niche. This proposed project is significant
because zebrafish models can fill critical gaps in our understanding of DIPG biology. This
knowledge ultimately has the potential to offer new strategies for the developments of the first
successful treatment of DIPG.
Status | Finished |
---|---|
Effective start/end date | 7/1/21 → 6/30/24 |
Funding
- ChadTough Defeat DIPG Foundation: $250,000.00
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