PACM-02 HISTAMINE RECEPTOR BLOCKADE REPROGRAMMES NEUROVASCULAR STATES AND SUPPRESSES CNS METASTATIC DISSEMINATION

Abstract

CNS metastatic dissemination is governed by interactions between tumour cells and host microenvironmental compartments, including the neurovascular unit and immune ecosystem. Epidemiological studies suggest antihistamine use is associated with reduced cancer-related morbidity, and histamine signalling has been implicated in tumour-associated immune suppression, suggesting pharmacological H1 receptor blockade may alter metastatic competence. We therefore investigated whether loratadine, a widely used H1 antihistamine, modulates neurovascular states and tumour dissemination in preclinical models of metastatic cancer and paediatric brain tumours. An orthotopic brain-tropic triple-negative breast cancer (4T1) model was used to examine the impact of loratadine on metastatic dissemination following surgical resection of primary tumours. Mice received acute or chronic loratadine with doxorubicin and were followed for survival and metastatic burden. Loratadine treatment after resection significantly improved survival compared with controls (median survival 30 vs 56 days, p<0.0001), while mice treated with loratadine prior to tumour implantation had a median survival of 80 days (p<0.0001). Notably, loratadine treatment was associated with reduced metastatic burden and altered metastatic distribution, with no detectable brain metastases in treated cohorts. Neurovascular analysis demonstrated early vascular fenestration in control brains prior to tumour formation, whereas loratadine-treated animals exhibited reduced vascular permissiveness. Loratadine was also assessed in orthotopic WNT medulloblastoma patient-derived xenografts, where it had a modest survival benefit but significantly reduced irradiation-associated metastatic dissemination. We next established a juvenile syngeneic SHH medulloblastoma mouse model with reproducible leptomeningeal dissemination, enabling interrogation of the developing neurovascular-immune niche. Early findings suggest a survival benefit with loratadine combined with radiotherapy, and ongoing studies incorporating immunophenotyping and single-cell transcriptomics will define immune mechanisms underlying these effects and evaluate combination strategies with immune checkpoint blockade. These findings suggest histamine receptor signalling contributes to neurovascular states that facilitate metastatic dissemination and that H1 receptor blockade may represent a tractable strategy to limit CNS spread.