# Biological Comparisons Among Three Derivative Models of Glioma Patient Cancers Under Microenvironmental Stress

> **NIH NIH U01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $790,576

## 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. This is particularly true for glioblastoma (GBM) where prognosis 
has increased only by 2-3 months over the last 75 years with a 5-year survival of less than 4%. Many promising 
preclinical studies have failed to live up to expectations when tested clinically. This problem is likely due to: a) 
limitations of the preclinical model system and b) lack of reliable biomarkers for proper patient selection. To 
address these issues, investigators are increasingly utilizing patient-­derived models of cancer (PDMC) coupled 
with comprehensive molecular profiling. However, differences in model composition, growth conditions, and 
other microenvironmental factors limit reliability of these models and hamper interpretation. We believe that a 
careful investigation of tumor microenvironmental (TME) stressors on 3 patient­derived models (xenolines) of 
GBM, namely xenografts (PDX), spheroid cultures (neurospheres), and human biomatrix embedded 3D 
microtumors, will provide insight into critical aspects of tumor biology that are influenced by model and TME. 
These models pre­ and post­ TME perturbagen will also be comprehensively profiled at the genomic, 
transcriptomic, and kinomic (global kinase activity assessment through a peptide substrate microarray) level to 
generate a similarity distance metric. We hypothesize that application of TME stressors to the PDMC’s will 
improve both molecular and biological fidelity of the respective models to that of the original tumor or parent 
xenoline that can be visualized and in silico tested using an advanced computational data modeling system 
(GeneTerrain). Our preliminary data generated from prior NIH funded projects indicate that our existing xenolines 
recapitulate all four molecular subtypes of GBM identified in The Cancer Genome Atlas while reproducing the 
key hallmarks of GBM when implanted orthotopically in immunocompromised mice. Importantly, we can grow 
disaggregated xenoline tumors in a novel three-dimensional (3D) culture system incorporating many cells of the 
tumor microenvironment to produce 3D microtumors suitable for higher throughput drug testing. Moreover, we 
have preliminary evidence that TME manipulation of BTICs or 3D microtumors (e.g., hypoxia or nutrient 
deprivation) promotes a more aggressive tumor phenotype in vitro and in vivo that is accompanied by changes 
in kinomic signatures. Therefore, we will: 1) Generate 3 PDMC models from existing xenolines as well as de 
novo GBM patient tumors with comprehensive omic testing to calculate similarity distance metrics among the 
models with corresponding biological assessments including growth, chemoradiation sensitivity, and stemness 
markers;; 2) Perform TME perturbagen testing of the derivative PDMCs (neurospheres and 3D microtumors) and 
determine impac...

## Key facts

- **NIH application ID:** 10247053
- **Project number:** 5U01CA223976-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Jake Yue Chen
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $790,576
- **Award type:** 5
- **Project period:** 2018-09-17 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247053

## Citation

> US National Institutes of Health, RePORTER application 10247053, Biological Comparisons Among Three Derivative Models of Glioma Patient Cancers Under Microenvironmental Stress (5U01CA223976-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247053. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*