Grants and Contracts Details
Description
PROJECT SUMMARY
Diffuse mid-line gliomas with H3K27M alteration (DMG-H3K27M) are the leading cause of pediatric brain
tumor-associated deaths. All DMG-H3K27M becomes resistant to radiation, the standard of care, and most
children succumb to their disease within 2 years of diagnosis. New treatment options are urgently needed. The
long-term goal of the applicant is to combine engineering and cancer cell biology to lead a research group that
advances extracellular vesicle (EV)-based drug delivery for central nervous system diseases like DMG-
H3K27M. The overall objectives in this project are to define how DMG-H3K27M derived EVs contribute to
radiation resistance within a heterogenous tumor and to develop EVs as a delivery vehicle for radiosensitizers
to the brain, while equipping the applicant with the skills to become a strong, independent cancer researcher.
Preliminary data indicate that subclones within DMG-H3K27M are inherently radiation resistant and can
release EVs that are readily taken up by radiosensitive cells in a receptor-mediated manner. These EVs
protect the recipient tumor cells from radiation-induced cell death. Therefore, the central hypothesis is that the
cargo of DMG-H3K27M extracellular vesicles, particularly microRNAs, drives radiation resistance within these
tumors and that targeting these factors can sensitize DMG-H3K27M cells to radiotherapy. Additionally, the
selective uptake of EVs DMG-H3K27M cells suggests that EVs can be exploited as a drug delivery tool. The
rationale for this research is that these findings will provide novel insights into mechanisms of radioresistance
in DMG-H3K27M and may result in new approaches to target this cancer. The hypothesis will be tested by
pursuing two specific aims: 1) Determine the mechanism of EV-mediated radioresistance in DMG-H3K27M
and 2) Engineer extracellular vesicles to effectively deliver radiosensitizers to DMG-H3K27M. The first aim will
be carried out as part of the dissertation research and will use patient-derived DMG-H3K27M cells, proteomics,
and chemical inhibitors to define the mechanism of EV uptake. Additionally, miRNA mimics and antagomirs will
be used to overexpress and silence miRNAs found in EV cargo to identify those miRNAs associated with
enhanced radioresistance in DMG-H3K27M. Targets will be validated using zebrafish xenograft models. The
second aim will encompass the post-doctoral research and focus on developing methods to engineer non-
tumor extracellular vesicles for specificity towards DMG-H3K27M and assessing their capability to cross the
blood-brain barrier to deliver radiosensitizers. The research proposed in this application is significant because
it will provide new insights into the role of tumor heterogeneity in driving therapy resistance. This project will
also identify new mechanisms of DMG-H3K27M radioresistance and develop an innovative strategy for drug
delivery to optimize the therapeutic efficacy of radiosensitizers in the brain, which ultimately may lead to
improve treatment outcomes for children with DMG-H3K27M.
Status | Active |
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Effective start/end date | 9/1/24 → 8/31/26 |
Funding
- National Cancer Institute: $35,602.00
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