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.
Law et al. (Wed,) studied this question.