Grants and Contracts Details
Description
Diffuse Intrinsic Pontine Glioma (DIPG) is a childhood brain cancer with a <1% survival rate. DIPG is an aggressive tumor that grows in the pons of the brain stem, which controls critical processes like heart rate, breathing, swallowing and vision. For the last 40 years, and today, the standard of care for DIPG is radiation therapy. This, at best, provides some symptom relief to patients as the tumor shrinks. However, it will inevitably regrow, and 90% of patients will die from DIPG within 2 years of diagnosis. Recent next-generation sequencing efforts show that each patient’s DIPG is genetically distinct with unique mutational profiles, so why every DIPG recurs after radiation therapy is an open question in the field. We believe this inherent treatment resistance is related to the cell-of-origin in DIPG, or the neural stem cell. Normal neural stem cells are necessarily long-lived, and harbor survival, quiescence, and resistance mechanisms.
We hypothesize that DIPG cells co-opt these survival mechanisms during the transformation process and, once the tumor is established, use them to survive radiation therapy
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By defining these cancer stem cell survival pathways, which should be common in all DIPG,
we can establish novel drug targets that could sensitize DIPG to radiation.
The goals of the project will be to 1) Define key genes and pathways that drive radiation resistance in DIPG. We will treat DIPG cancer stem cells, isolated from untreated, primary patient samples with, radiation therapy and identify which genes are recurrently activated as each DIPG cancer stem cell population becomes radio-resistant, these pathways will be targeted to identify which genes are critical drivers of DIPG survival. 2) Assess the role various TP53 mutations in radiation resistance. TP53 is a tumor suppressor involved in DNA repair and is especially critical in inducing apoptosis in radiation treated cells. In DIPG, TP53 is commonly mutated in the DNA binding domain. We will define what role common TP53 mutations plays in DIPG radio-resistance, whether they are loss-of-function or altered function, and whether TP53 function can be restored in DIPG. 3) Determine the impact of the tumor microenvironment on DIPG cancer stem cell survival. Stem cells rely heavily on their niche for survival and DIPG in particular grows intertwined within its microenvironment. Using a novel fluorescent reporter system, we will xenograft human primary DIPG stem cells into the zebrafish pons, track how they interact with the cells within the neural niche, and isolate cells to examine how gene expression of the niche changes in response to healthy and irradiated tumor. Data from this aim may open up entirely new avenues of research for druggable targets in DIPG.
In total, this research extends the impact of our parent grant by addressing the major clinical issue in DIPG, radiation resistance, and approaching it using our laboratory’s unique expertise in cancer stem cells and zebrafish models.
We also leverage key collaborations to obtain treatment naïve patient derived cell lines from DIPG biopsy tissue, which are rare. Once drug targets are found and validated in this supplement, the PHOTACS developed in the parent grant against BRD4 can be easily adapted to the new target for pre-clinical trial and beyond.
Status | Active |
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Effective start/end date | 7/1/24 → 6/30/25 |
Funding
- KY Cabinet for Health and Family Services: $148,932.00
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