# A 3D ex vivo orthotopic xenograft screening platform to identify radiosensitization targets and druggability in glioma

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $175,088

## Abstract

Critical challenges that impede advances in glioma therapy continue to be the physiological relevance and
throughput of preclinical models, and the limited success of single molecule/pathway targeting strategies, likely
due to intra-tumoral heterogeneity/rapid adaptive resistance. It has become increasingly apparent that
conventional, high throughput 2-D cell culture models diverge substantially from bona fide primary brain
tumors. Advanced preclinical models such as tumorsphere and flank patient-derived xenograft or "PDX"
models offer improved retention of some native tumor cell properties, but require weeks to months to establish
and still lack native, immune-intact 3-D brain tissue context for glioma cell growth. Moreover, experimental
accessibility for these systems is limited, especially for PDX models, where real-time monitoring of tumor
growth is precluded, and studies are expensive and time-consuming. As a result, targets and pathways
identified in these systems have to date not translated into effective therapeutic strategies. Our most effective
current glioma therapy thus continues to be surgical debulking followed by DNA damage delivered by radiation
and alkylating chemotherapy. Median overall survival, however, remains at a dismal ~16 months.
 In this context, the development of effective radiosensitizing agents presents a major opportunity to
leverage the current standard-of-care for significantly improved patient outcome. To address this urgent unmet
need, the studies proposed here will take advantage of a novel, scalable, immune-competent 3-D organotypic
brain slice culture model of glioma we have developed that easily integrates with laboratory models of radiation
therapy to create a discovery platform for radiosensitization and resistance targets in glioma. This platform
supports both genetic and drug discovery approaches, and we have validated its effective integration with
radiation therapy methods at both the target and drug therapy levels. We will use this platform to accomplish a
CRISPR-based radiosensitization screen of druggable targets, and to validate their druggability in this model
using direct chemical inhibition. Finally, as the platform includes native immune cells as well as resident
neurons and glia, we will be able to simultaneously evaluate immune responses and the "therapeutic index" of
novel radiation/compound therapeutic combinations directly at the tissue site of drug action.
 This new platform combines extensive experience of the Co-PIs in developing elevated-throughput brain-
slice assays for drug discovery, and in large-scale genetic screening and both research and clinical radiation
oncology. Our goal is to demonstrate and validate this novel approach as an ex vivo brain-slice "orthotopic"
discovery platform to identify radiosensitization targets and to test their druggability for rapid clinical translation
towards more effective glioma therapy.

## Key facts

- **NIH application ID:** 9852570
- **Project number:** 5R21CA226483-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Scott R Floyd
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $175,088
- **Award type:** 5
- **Project period:** 2019-02-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852570

## Citation

> US National Institutes of Health, RePORTER application 9852570, A 3D ex vivo orthotopic xenograft screening platform to identify radiosensitization targets and druggability in glioma (5R21CA226483-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852570. Licensed CC0.

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