# GBM Avatar Screening Paradigm for Rational Pharmacokinomic Glioma Therapy

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $381,264

## Abstract

This exploratory research project will utilize an alternative strategy that can be generally applied to select the
most appropriate drug or drug combination to treat highly aggressive malignant brain tumors called glioblastoma
multiforme (GBM). GBMs are diagnosed in over 17,000 patients each year and are essentially incurable.
Despite over 75 years of research, our "best" standard of care therapies involve surgical resection, radiation and
chemotherapy, but are not curative, providing only a 4% 5-year survival rate with an annual death toll of 12,000+.
Most cellular functions are regulated inside all cells by kinases that enzymatically phosphorylate other proteins.
Kinase-phosphorylated proteins are activated or suppressed to "drive" most cellular processes (e.g.,
proliferation, metastasis, survival) and to modulate cellular responses to therapies and other stresses. Small
molecule inhibitors (SMIs) represent the fastest growing class of new drugs that block activities of cellular
kinases, but are somewhat promiscuous in their effects. There are 518 known human protein kinases and many
are either active in the cell (unregulated) or are activated by other kinases. Kinases are auto-phosphorylated or
phosphorylated by other kinases serially to generate “cascades” down so called "signaling pathways". Inhibition
of the right combination of kinases in certain signaling pathways will lead to death of tumor cells. We have a
panel of human GBM Patient-Derived Xenolines (PDX) that were established in mice from surgical tumor tissues
and were grown in the brains of mice, harvested and cryopreserved. Half (~27) have been extensively
characterized genomically, transcriptomically and kinomically and form the “Reference Panel”; the other half
(~24) are uncharacterized, at low passage and serve as our “Validation Panel”. These PDX will serve as patient
"avatars" for drug selection. We will extract proteins from frozen tissues of six (6) of the low-passage Reference
Panel PDX tumors to measure the ability of four (4) selected (blood-brain-barrier permeable) SMIs, to inhibit
specific kinases that are enzymatically active in tumors. We will use ex vivo testing in which a small amount (1-
15g) of protein from each PDX is `spiked' with 1-20M of each SMI and analyzed in the PamStation-12 that can
quantify enzymatic activity of 518 protein kinases and determine if a SMI "hits its target" or has “off-target” effects.
The selection of potentially effective SMIs will be validated using low passage PDX for which the kinome profile
will be determined, then matched to tumors in the Reference Panel. This will mimic the clinical situation in which
a patient's tumor is kinomically profiled, and that profile matched to that of PDX that will have a previously defined
SMI-responsiveness profile. We anticipate that the data developed in this exploratory research will demonstrate
that this “avatar” approach can accurately predict potential therapeutics or combinations thereof for ...

## Key facts

- **NIH application ID:** 10043740
- **Project number:** 1R21CA252382-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Christopher D Willey
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,264
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10043740

## Citation

> US National Institutes of Health, RePORTER application 10043740, GBM Avatar Screening Paradigm for Rational Pharmacokinomic Glioma Therapy (1R21CA252382-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10043740. Licensed CC0.

---

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