# Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $433,375

## Abstract

Brain metastases account for decreased survival, increased morbidity, impaired cognition and poor quality of life
for patients with lung cancer. Effective therapies for the treatment of brain metastases are lacking due in part to
limited knowledge of the molecular mechanisms that regulate colonization of the brain parenchyma. Lung cancer
is the leading cause of cancer mortality in the U.S., with an overall five-year survival rate of ~16%. It is estimated
that ~ 234,030 new cases and ~ 154,050 deaths of lung cancer per year. Notably, ~40% of lung cancer patients
have metastases at the time of diagnosis, and exhibit the highest prevalence of brain metastasis (40-60 %)
among all cancer types. Current therapies to treat lung cancer brain metastases have proven ineffective due to
variable, transient and incomplete responses. We recently reported that allosteric inhibitors of the ABL kinases
cross the blood-brain barrier (BBB) and markedly impair the growth of brain metastases. Enhanced expression
of ABL and downstream target genes is linked to shortened survival of lung adenocarcinoma patients. We have
identified specific ABL-regulated transcription factors that mediate the brain metastatic potential of lung cancer
cells by regulating reciprocal crosstalk between brain metastases and neural cells. An unexpected role of this
ABL-regulated transcription network is that it promotes expression of neuronal signatures in brain metastatic
lung cancer cells. Acquisition of “neuronal mimicry” by lung tumors is a potential mechanistic adaptation to
achieve effective colonization and outgrowth in the brain by co-opting the function of neuronal cells, astrocytes
and microglia. In this regard, we found that inhibition of ABL kinases in lung cancer cells impairs deleterious
inflammatory responses of brain microglia cells. The overall hypothesis is that ABL-regulated transcription
networks promote brain metastasis, and that inhibition of ABL signaling enhances tumor cell vulnerabilities by
disrupting crosstalk between brain metastatic cells and resident neural cells in the brain tumor microenvironment.
To evaluate this hypothesis, we propose three specific aims: 1) Define the ABL-regulated transcription networks
that promote lung cancer brain metastasis and the mechanisms whereby inactivation of ABL kinases impairs
brain metastasis. 2) Evaluate whether inactivation of ABL kinases impairs metastatic colonization of the brain
parenchyma by disrupting tumor-neural cell crosstalk, while concomitantly blunting tumor-induced neurotoxicity.
3) Define the transcriptional landscape of lung cancer brain metastases and assess whether ABL-regulated
transcriptomic signatures identify lung cancer types that metastasize to the brain. To this end we will employ
state-of-the-art transcriptomic technologies to evaluate transcriptional changes, not only in brain metastasis, but
also among neural cell types in the surrounding brain parenchyma. Results from these experiments will reveal...

## Key facts

- **NIH application ID:** 10164550
- **Project number:** 1R01CA246133-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Ann Marie Pendergast
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $433,375
- **Award type:** 1
- **Project period:** 2021-03-05 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164550

## Citation

> US National Institutes of Health, RePORTER application 10164550, Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis (1R01CA246133-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10164550. Licensed CC0.

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