# Uncovering actionable signaling pathways required for solid tumor brain metastasis

> **NIH NIH K00** · DUKE UNIVERSITY · 2020 · $81,525

## Abstract

ABSTRACT
Despite the emergence of targeted therapies and immune checkpoint inhibitors for the treatment of diverse solid
tumor types, the metastatic spread of tumor cells to distant organ sites remains the primary determinant of
cancer-related mortality. As patient survival increases owing to improved management of primary tumor burden,
of particular concern is the rising incidence of brain metastases which with few exceptions reduce patient survival
to the order of weeks or months. Metastases to the brain are most commonly seen in patients with tumors of the
lung, breast, and melanoma. Therapies targeting “driver” mutations and gene amplifications such as EGFR
(lung), HER2 (breast), and RAF/MEK (melanoma) have been ineffective at treating brain metastases owing to
transient responses and lack of blood-brain barrier penetrance. The use of checkpoint inhibitors for the
management of brain metastases has also been met with limited clinical success. As it stands, no effective
therapies exist for patients suffering from brain metastases, therefore the discovery of novel strategies by which
to treat metastatic disease within the brain is an urgent clinical need. This proposal describes our ongoing work
to characterize a novel AXL-ABL2-TAZ signaling axis in brain-metastatic lung cancer cells through the
implementation of in vivo mouse models of brain metastasis combined with follow-up mechanistic studies. We
find that activation of this signaling axis drives expression of brain metastasis-associated genes which allow
disseminated tumor cells to adapt and survive in the brain microenvironment. Importantly, targeted inhibition of
AXL or the ABL kinases impairs brain-metastatic outgrowth and significantly extends survival in brain metastasis-
bearing mice. Lastly, I describe future studies to be conducted as a postdoctoral candidate by combining my
current expertise in cell signaling and the use of in vivo mouse models with high-throughput functional genomics
platforms to unbiasedly identify the molecular mediators governing solid tumor metastasis to the brain.

## Key facts

- **NIH application ID:** 10165993
- **Project number:** 4K00CA245732-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jacob Peter Hoj
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $81,525
- **Award type:** 4N
- **Project period:** 2019-09-09 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165993

## Citation

> US National Institutes of Health, RePORTER application 10165993, Uncovering actionable signaling pathways required for solid tumor brain metastasis (4K00CA245732-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10165993. Licensed CC0.

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