# Credentialing next-generation human glioma models for precision therapeutics

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $131,545

## Abstract

ABSTRACT
This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-
CA-23-045. Despite notable successes in other cancers, precision therapeutics have failed in EGFR-driven
gliomas, the most common and deadly primary brain tumors. Reasons for failure include the lack of
preclinical models that faithfully recapitulate the biology of EGFR-driven gliomas and adaptive responses to
therapy. Through our multi-PI (MPI) parent award R01 CA258248, we are developing and molecularly
credentialing novel EGFR mutant-driven human glioma models for use in preclinical development of
tyrosine kinase inhibitor (TKI)-based therapies. The foundation of our modeling work comes from the
Furnari Lab (UCSD), who developed a novel platform for engineering glioma models from human induced
pluripotent stem cells (iPSC) using CRISPR genome editing. The Miller Lab has extensive experience in
small molecule experimental therapeutics using genetically engineered (GE) glioma models, next-
generation sequencing, and proteomics. Our parent award proposed to leverage our established
collaboration with the Johnson Lab (UNC) to profile kinase expression en masse using multiplex inhibitor
beads coupled with mass spectrometry (MIB-MS). We previously used this approach to show that dynamic
kinome reprogramming contributes to targeted drug resistance in glioma models. In this Multi-PI
supplement, we will extend our originally proposed work through integration of two distinct, but
complementary kinome profiling approaches. The Johnson Lab has developed an updated version of MIB-
MS termed SureQuant. MIB-MS requires affinity-based enrichment of active kinases using broad-spectrum
inhibitors chemically coupled to Sepharose beads and is limited to relative quantification of kinase
expression. SureQuant uses isotopically “heavy” peptides, designed from MIB-enriched, proteolytically
digested human kinases, and parallel reaction monitoring (PRM) to absolutely quantify kinase expression
in otherwise un-enriched protein samples. This advance will be coupled with a second complimentary
approach: the PamStation technology from the Kinome Core (Willey Lab) at UAB. This approach monitors
the kinetics of tyrosine or serine/threonine kinase activity (phosphorylation) in real time using specific
peptide substrates immobilized on microchips. Thus, whereas SureQuant accurately measures kinase
expression, PamStation monitors substrate-level kinase activity. We hypothesize that a combination of
these two approaches, and bioinformatic integration of the resulting data, will provide novel insights into the
glioma kinome and its dynamic response to targeted EGFR TKI.

## Key facts

- **NIH application ID:** 10830654
- **Project number:** 3R01CA258248-02S1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Frank Furnari
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $131,545
- **Award type:** 3
- **Project period:** 2023-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830654

## Citation

> US National Institutes of Health, RePORTER application 10830654, Credentialing next-generation human glioma models for precision therapeutics (3R01CA258248-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10830654. Licensed CC0.

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