
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.021
vdae090.021
Final Category: Basic Science Leptomeningeal Disease
AcademicSubjects/MED00300
AcademicSubjects/MED00310
BSLM-11 ESTABLISHING AND VALIDATING IN VIVO MODELS FOR LEPTOMENINGEAL METASTASES IN BREAST CANCER: INSIGHTS AND THERAPEUTIC IMPLICATIONS
Kumar Dinesh Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Silvestri Vanesa Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Robinson Christina Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

Difilippantonio Simone Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

Steeg Patricia Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i7i7
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

Leptomeningeal metastases (LM), characterized by cancer cell growth in the linings of the brain and spinal cord, and the cerebrospinal fluid (CSF) compartment, have a dire prognosis represent 5-15% of central nervous system metastases. LM occur in all subclasses of breast cancer and are currently treated with intrathecal methotrexate or liposomal cytarabine or radiation therapy. Despite initial response to current treatments, median survival remains poor. Relatively little is known on the development of LM, due to the lack of adequate mouse models. This study aimed to develop and validate in vivo models of LM and to use them to credential potential therapies. Three breast cancer models were established using intracisternal injections of tumor cells covering the HER2+, ER+ lobular and triple negative breast cancer subtypes. The HER2+ model was produced from the JIMT-1-BR cell line that previously was enriched for metastasis to the brain parenchyma, reflecting clinical observations of concurrent parenchymal and LM spread. Multiple endpoints were implemented to assess disease progression: bioluminescence imaging, histopathology, MRI, tumor cells in CSF. Bulk RNA sequencing on all LM-tropic cell lines revealed significant alterations in cytokine-cytokine receptor interactions, calcium signaling pathways, cell adhesion molecules, and TNF signaling pathways across all models. Notably, several genes including PORCN, PGBD5, FAM43A and FHOD3 were differentially expressed and consistently alter across all models. Validation of these key genes is underway. For the JIMT-1-BR HER2+ model, efficacy studies compared standard therapy (trastuzumab + paclitaxel) with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd). T-DXd (10 mg/kg, iv q3w) demonstrated superior efficacy with extended survival and reduced extent of edema on MRI. This study established and validated three in vivo models of LM colonization. These models, incorporating diverse endpoints, and drug testing capabilities, offer a valuable platform for identifying novel therapeutic strategies to combat this aggressive form of breast cancer progression.
==== Body
pmc
