# Defining and targeting a novel pathway for central nervous system leptomeningeal metastasis

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $362,776

## Abstract

ABSTRACT
 Cancer metastases to the leptomeninges (LM) are difficult to treat, create significant morbidity, and
predict extremely poor survival. There are currently no molecularly targeted approaches to prevent LM disease
involvement. LM metastases are frequent in hematologic malignancies such as acute lymphoblastic leukemia
(ALL), and the incidence in solid tumors is rising. We recently reported a novel mechanism whereby ALL cells
invade the central nervous system (CNS) LM by migrating along the abluminal surface of emissary blood
vessels that bridge the vertebral and calvarial bone marrow and subarachnoid spaces. ALL cells hijack a
neural stem cell developmental migration pathway involving α6 integrin receptor and laminin binding
interactions in order to crawl along the laminin-rich basement membrane of this unique vasculature. These
vessels pass from the bone marrow through apertures in the vertebral or calvarial bone to directly enter the
LM. Malignant cells expressing the laminin receptor, α6, invade along the external surface of this bridging
vasculature in an integrin-dependent fashion, bypassing the peripheral circulation and the blood brain barrier to
efficiently metastasize to the LM. This finding explains the clinical observation that LM metastases frequently
occur in the absence of brain parenchymal disease involvement. In this proposal, we will define the signaling
events that are activated in leukemic cells upon α6 integrin-laminin engagement, determine the role of α6
integrin-laminin interactions in breast cancer leptomeningeal metastasis, and test the efficacy of downstream
PI3K inhibition to target this pathway in mouse models of ALL and breast cancer LM metastasis. These studies
will provide new mechanistic insight into a poorly understood biologic phenomenon and a therapeutic approach
to an area of high unmet clinical need.

## Key facts

- **NIH application ID:** 10079480
- **Project number:** 5R01CA234580-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Dorothy A Sipkins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $362,776
- **Award type:** 5
- **Project period:** 2020-01-06 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10079480

## Citation

> US National Institutes of Health, RePORTER application 10079480, Defining and targeting a novel pathway for central nervous system leptomeningeal metastasis (5R01CA234580-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10079480. Licensed CC0.

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