# Glioblastoma tumor microenvironmental influence on acquired and inherent cancer therapy resistance.

> **NIH NIH U01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $297,715

## Abstract

PROJECT SUMMARY/ABSTRACT:
Current methods of preclinical testing of potential therapeutics have been, for the most part, underwhelming in
terms of their ability to yield a clinical impact. Moreover, preclinical investigation of cancer therapy resistance
mechanisms faces similar challenges due, at least in part, to both limitations of the preclinical model systems
and lack of reliable biomarkers. A prime example is glioblastoma (GBM) with few therapeutic options yielding
incredibly poor outcomes (5-year survival <4%) despite nearly eight decades of research. Indeed, current
standard of care (SOC) therapy includes maximal safe surgical resection followed by fractionated irradiation and
temozolomide (TMZ) chemotherapy. These patients tend to fall into two categories: those who have inherent
resistance to radiation and TMZ and those who acquire resistance to those therapies (typically within 6 months).
While many groups have tried to develop more effective therapeutics or overcome GBM resistance mechanisms,
virtually all attempts have relied on highly artificial models under major growth promoting conditions that select
for highly proliferative tumors that no longer resemble the patient’s tumor. To address these issues, investigators
are increasingly utilizing patient-derived models of cancer (PDMC) coupled with comprehensive molecular
profiling to build more reliable models for examining therapeutic resistance and for developing novel therapies.
Building on a series of collaborations and funded projects, our investigative team has developed a large panel
of GBM xenografts (PDX) that can be cultured without serum as derivative PDMC models including spheroids
(neurospheres) and matrix-embedded microtumors. Our parent U01 (U01-CA223976) seeks to investigate tumor
microenvironmental (TME) stressors on these 3 PDMC models in terms of molecular biology (e.g., transcriptome
and kinome similarity) and phenotype (e.g., radiation and TMZ response) fidelity. In this U01 Revision
Application, we seek to extend our work by developing new in vitro and in vivo models to investigate inherent
and acquired resistance to SOC GBM therapy. We have characterized baseline in vivo radiation and TMZ
sensitivity in 20 of our GBM PDX and have developed 8 radiation resistant and 5 TMZ resistant isogenic lines
from initially sensitive tumors. Transcriptomic and kinomic testing of these pairs have identified several genes
and kinases associated with resistance. We will leverage this very unique resource to examine SOC therapeutic
resistance. Aim 1 utilizes a high-throughput geospatially controlled 3D bioprinting system to replicate in vivo
conditions by using co-culture of PDX cells and vascular endothelial cells in a variety of matrices with and without
other TME stressors (e.g. hypoxia and nutrient deprivation seen in patients). These constructs will be tested in
up to 384-well format to facilitate inhibition of high-priority targets of SOC resistance as identified from our
tr...

## Key facts

- **NIH application ID:** 10046398
- **Project number:** 3U01CA223976-03S1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** G. YANCEY GILLESPIE
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $297,715
- **Award type:** 3
- **Project period:** 2018-09-17 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046398

## Citation

> US National Institutes of Health, RePORTER application 10046398, Glioblastoma tumor microenvironmental influence on acquired and inherent cancer therapy resistance. (3U01CA223976-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10046398. Licensed CC0.

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