# Small molecule inhibitors with a therapeutic window for EGFR signaling variants in glioblastoma

> **NIH NIH U19** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $196,169

## Abstract

Project Summary
 The epidermal growth factor receptor (EGFR) gene is mutated or amplified in over half of GBMs, and its
mutation and focal amplification correlate with a more aggressive disease course. However, EGFR-directed
tyrosine kinase inhibitors (TKIs) have failed to show efficacy in this disease and these failures cannot be
attributed strictly to poor brain penetrance. We posit that the failure to date of EGFR TKIs for GBM reflects lack
of a therapeutic window. A lesson learned from application of EGFR inhibitors in non-small cell lung cancer
(NSCLC) is that mutant-selectivity is absolutely required. Without selectivity, systemic inhibition of wild-type
(WT) EGFR signaling is the dose-limiting toxicity. In NSCLC, activating mutations in the tyrosine kinase domain
confer enhanced sensitivity to certain EGFR TKIs relative to WT EGFR, allowing true mutant-selective
inhibition. The EGFR genetic aberrations in glioblastoma (GBM) create constitutive, ligand-independent
signaling via signal generating domains that are almost exclusively WT in structure. Our objective is to create
EGFR TKIs with a therapeutic window for aberrant EGFR signaling in GBM. We have two specific aims.
 Aim 1, is to test the hypothesis that an EGFR TKI with an allosteric mechanism of action will selectively
block ligand-independent EGFR signaling in GBM while sparing ligand-activated EGFR systemically, thereby
providing a therapeutic window that allows effective treatment of EGFR-driven GBMs. In preliminary studies,
we have developed small-molecule allosteric inhibitors that potently inhibit WT EGFR (IC50 < 100 nM in
biochemical assays) and have a good oral mouse PK profile and are brain-penetrant. Guided by efficacy
studies in patient-derived GBM neurosphere and xenograft models, we expect to identify a compound suitable
for clinical development in the first grant year, to enable clinical translation in the out years.
 Aim 2, exploits CM93, a novel third generation EGFR TKI that is highly brain-penetrant – so much so
that it actually displays a positive brain/plasma ratio. We will test the hypothesis that CM93 can provide a de
facto “tissue-based” therapeutic window allowing effective inhibition of EGFR in the tumor with relative sparing
of the receptor systemically. Towards this end, we will conduct a first-in-human, phase 1, dose-escalation and
dose-expansion study, as well as a surgical “window of opportunity” study to determine the maximum tolerated
dose, evaluate the safety, pharmacokinetics, pharmacodynamics and clinical effects of orally administered
CM93 in subjects with recurrent glioblastoma characterized by EGFR mutation or amplification.
 Studies on clinical materials will be facilitated by our Pharmacological and Genomics Imaging Core
(PGIC). The PGIC will allow us to quantify intra-tumoral accumulation of CM93 using MALDI mass
spectrometry imaging and to define the impact of CM93 treatment on tumor heterogeneity using single cell
sequencing. Collectively, t...

## Key facts

- **NIH application ID:** 10306230
- **Project number:** 1U19CA264504-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MICHAEL J ECK
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $196,169
- **Award type:** 1
- **Project period:** 2021-09-21 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306230

## Citation

> US National Institutes of Health, RePORTER application 10306230, Small molecule inhibitors with a therapeutic window for EGFR signaling variants in glioblastoma (1U19CA264504-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10306230. Licensed CC0.

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