# Integrated ligand and target discovery by chemical proteomics for glioblastoma treatment.

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $641,594

## Abstract

PROJECT SUMMARY
The epidermal growth factor (EGFR) oncogene is amplified and drives tumor growth in 55% of adult
glioblastomas (GBMs). However, EGFR inhibitors have failed to demonstrate clinical benefit in GBM, presenting
one of the most fundamental challenges facing the field of neuro-oncology. As highlighted by the National Cancer
Institute’s recent think tank on progress in GBM, despite clear signals about the genomic underpinnings of GBM,
including the high frequency of EGFR amplification, new drug development programs have stalled because of
the high risk of clinical failures. Intra-tumoral genetic heterogeneity, and the poor brain-plasma ratios of many
drug candidates, are thought to play a major role in clinical failure. Building on the team’s recent discoveries
demonstrating that EGFR is amplified almost exclusively on extrachromosomal DNA particles (ecDNA), driving
intra-tumoral genetic heterogeneity, accelerated tumor evolution, and EGFR inhibitor resistance, and their
discovery of actionable metabolic dependencies that arise when EGFR becomes amplified, this proposal will
identify proteins on which EGFR-amplified GBMs selectively depend for survival, even in highly heterogeneous
tumors. This proposal integrates a hypothesis-driven approach with unbiased discovery using activity-based
protein profiling (ABPP). In clinically relevant patient-derived models of GBM, this proposal takes a chemistry-
first approach to discover both actionable dependencies that arise when EGFR is amplified and ligands that
engage these proteins, which can be made to be highly brain-penetrant. By deploying fully functionalized (FF)
small-molecule libraries to enable direct progression from phenotypic screening to target identification in living
GBM cells, including in patient-derived GBMs with amplified EGFR, this proposal is poised to inform actionable
therapeutic targets for patients in vivo. The proposed integrated approach provides a rapid route towards
initiating new drug development that directly addresses the fundamental challenges of GBM.

## Key facts

- **NIH application ID:** 10880499
- **Project number:** 5R01CA238249-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** BENJAMIN F CRAVATT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $641,594
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880499

## Citation

> US National Institutes of Health, RePORTER application 10880499, Integrated ligand and target discovery by chemical proteomics for glioblastoma treatment. (5R01CA238249-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10880499. Licensed CC0.

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