What type of study is this?

This is a Experimental Study study (also classified as: Cohort Study).

October 5, 2025Open Access

Os06.4.a Homoharringtonine Shows Efficacy Against Melanoma Leptomeningeal Disease in Preclinical Models Using Patient-Derived Cerebral Spinal Fluid Tumor Cells

Key Points

Homoharringtonine significantly extended survival in mice with melanoma leptomeningeal disease while maintaining well-being.
Among 1,436 evaluated small molecules, about 1.4% demonstrated complete cytotoxicity, with homoharringtonine showing remarkable efficacy.
The study employed patient-derived tumor cells and xenograft models, creating valuable tools for therapeutic exploration in leptomeningeal disease.
Identifying homoharringtonine as a targeted therapy highlights its potential to repurpose FDA-approved drugs for aggressive melanoma treatment.

Abstract

Abstract BACKGROUND Leptomeningeal disease from melanoma (M-LMD) is a rare, aggressive metastasis with limited treatment options and a poor prognosis. One major obstacle in therapeutic development is the scarcity of clinically relevant models, particularly patient-derived circulating tumor cells from cerebrospinal fluid (PD-CSF-CTCs). To address this, we developed protocols for collecting CSF and tissue from M-LMD patients, successfully propagated PD-CSF-CTCs ex vivo, and generated patient-derived xenograft models. These tools enabled comprehensive proteomic and transcriptomic analyses to identify M-LMD-specific pathways, supporting the search for targeted therapies. MATERIAL AND METHODS PD-CSF-CTCs were isolated and expanded from M-LMD patient samples. We screened 1,436 FDA-approved small molecules using a high-throughput 384-well assay to identify compounds that inhibited tumor cell proliferation. Top hits were evaluated in vivo using intrathecal (IT) administration in xenograft models. RESULTS Twenty compounds (~1.4%) showed complete cytotoxicity in both PD-CSF-CTCs and murine melanoma lines. Among the most potent were ponatinib (EC₅₀: 1.85-4.06×10⁻⁶), sorafenib (9.57-9.77×10⁻⁶), ceritinib (1.84-2.05×10⁻⁶), and homoharringtonine (HHT; 3.63-4.11×10⁻⁸). HHT, a plant-derived semisynthetic cephalotaxine ester, was selected for in vivo validation due to its strong cytotoxicity and ability to cross the blood-brain and blood-CSF barriers. In a randomized murine M-LMD model, daily IT HHT (24.0 μg) was well-tolerated, significantly extended survival (P 0.001, Mantel-Cox test), and led to complete responses in 27% of mice, with preserved weight and motor function. CONCLUSION This study introduces a robust preclinical platform for identifying effective treatments for M-LMD. Our findings highlight the promise of repurposing FDA-approved HHT as a therapeutic option. Future work will focus on elucidating HHT’s molecular mechanisms and testing its efficacy across other LMD subtypes, such as those arising from breast and lung cancers.

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