# Project 3: Identifying and targeting mediators of CNS metastasis from lung cancer

> **NIH NIH P50** · YALE UNIVERSITY · 2023 · $380,886

## Abstract

PROJECT SUMMARY
 Lung cancers are the major source of metastasis in the central nervous system (CNS). There is an important
gap in our understanding of how brain metastases respond to therapies and what mechanisms sustain metastatic
tumors in the CNS. Historically, the blood brain barrier has been viewed as an impediment to systemic drugs,
and novel brain penetrant agents such as the mutant EGFR inhibitor osimertinib have been developed. However,
despite improved clinical responses with these agents, brain metastases still progress, and it is unknown how
perturbations in the brain tumor microenvironment (TME) can be leveraged for more effective treatments in
patients with CNS disease. We have developed novel methods to molecularly characterize human cerebral
spinal fluid (CSF) as well as distinguish tumor from stromal gene alterations of brain metastasis in vivo. Our
approaches uncover genetic mutations as well as brain TME induced alterations that converge onto cooperating
pathways, such as those regulated by VEGF, NOTCH, β-catenin and PI3K. We hypothesize that these
molecular alterations: 1) cooperatively drive NSCLC brain metastasis and drug resistance in the brain, 2) are
clinically actionable, and 3) are more accurately detected in human CSF or brain biopsies, due to divergent
genetic evolution and TME induced adaptation of brain metastasis.
 Our hypothesis will be studied in 3 independent yet complimentary aims. In Aim1, we propose to collect
human CSF from craniotomies as well as lumbar punctures of lung cancer patients with brain metastases who
will be undergoing a bronchoscopic biopsy. By comparing the mutational landscape of matched CSF, plasma
and tumor tissue, we will molecularly characterize humans with asymptomatic brain metastasis. Moreover, we
will use novel orthotopic patient derived xenograft models (PDXs) to determine if brain metastasis progression
and drug response correlates with co-occurring mutations identified in human CSF. In Aim 2, we will test the
novel hypothesis that an activated brain microvasculature enhances the survival of drug resistant tumor cells via
stromal induced NOTCH signaling in vivo. We will assess if novel bi-specific agents which simultaneously inhibit
VEGF and NOTCH can delay brain metastasis progression and/or improve osimertinib response in pre-clinical
models. Using human biospecimens, we will correlate the expression of VEGF and NOTCH pathway
components with brain metastatic relapse. In Aim 3, we will conduct a clinical trial combining a mutation specific
TKI (osimertinib) with a brain vascular targeting agent (bevacizumab) in treatment naïve lung cancer patients
with EGFR mutant tumors and CNS disease. Finally, molecular markers (including those studied in Aims 1 and
2) of response or resistance to this combination will be identified by analyzing CSF, plasma and tumor biopsies.
 This proposal will help uncover the biological basis of brain metastasis relapse. Importantly, our study will
generate...

## Key facts

- **NIH application ID:** 10690081
- **Project number:** 5P50CA196530-09
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Don X Nguyen
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $380,886
- **Award type:** 5
- **Project period:** 2015-08-26 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690081

## Citation

> US National Institutes of Health, RePORTER application 10690081, Project 3: Identifying and targeting mediators of CNS metastasis from lung cancer (5P50CA196530-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10690081. Licensed CC0.

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