We recently revealed new insights on the growth of on the growth of craniopharyngioma and identified a potential therapeutic treatment. This work was published online in Science Translational Medicine on Dec 18th, 2024.
Craniopharyngioma, a benign yet highly invasive tumor occurring along the hypothalamus-pituitary axis, presents a unique clinical challenge. Despite its non-malignant nature, the tumor's particular location frequently leads to severe endocrine and metabolic complications. At times, the craniopharyngioma invades the hypothalamus and pituitary gland, resulting in endocrine dysfunction and metabolic disorders such as obesity, diabetes mellitus, hypothyroidism, diabetes insipidus. In severe cases, it can cause life-threatening conditions. Currently, surgical resection remains the primary therapeutic option, but it carries substantial risks, a high recurrence rate and significant postoperative complications.
To tackle these challenges, we generated genetically-engineered mouse models, adopted a multi-pronged approach to explore craniopharyngioma growth and identified a promising small molecule for chemotherapy.
Animal Modeling to Recapitulate Craniopharyngioma
Our team previously identified the cellular origins of papillary craniopharyngioma, as detailed in our work published in Nature Communications. Building on this achievement, we collected tumor samples from patients for whole-exome sequencing, revealed the tumor’s mutational landscape and then developed two sophisticated animal models. These models faithfully recapitulate the imageological, histological, phenomic, and transcriptomic characteristics of human craniopharyngioma. These models successfully mimic the pathological progression observed in patients, providing an invaluable platform for studying tumorigenic mechanisms and developing therapeutic interventions.
High-throughput Drug Screening Identifies an Efficient Drug Candidate
Using our animal models, our team established craniopharyngioma cell lines and screened over 3,000 compounds to identify drugs with potential anti-tumor effects. for their potential antitumor effects. Among the 74 top hits, one stood out: amlodipine besylate, a calcium channel blocker commonly prescribed for hypertension. Surprisingly, this routine medication showed potent antitumor effects in preclinical animal models.
Amlodipine’s established safety profile and widespread use as a cardiovascular drug make it a prime candidate for repurposing. Its efficacy lies in its ability to inhibit calcium signaling pathways in tumor cells. By blocking calcium transients, amlodipine effectively disrupts the chemical synaptic transmission between hypothalamic neurons and tumor cells.
Neural Regulation of Craniopharyngioma Cell Growth
While bulk, single-cell and spatial transcriptomic analyses revealed an enriched transcriptional program related to synaptic transmission in the mouse tumors, their immunostaining and electron microscopic results further demonstrated synaptic contacts between hypothalamic neurons and tumor cells. Using chemogenetic techniques, the researchers modulated the activity of hypothalamic neuroendocrine neurons in their animal models. They found that enhanced neuronal activity accelerated tumor growth, while reduced activity inhibited it.
These findings highlight the remarkable adaptability of craniopharyngiomas, which hijack hypothalamic neurons and leverage neurotransmitters to enhance their growth and aggressiveness. This work not only deepens our understanding of neuron-to-tumor interactions but also underscores the potential of disrupting neuron-tumor crosstalk as a viable therapeutic strategy.
Clinical Implications
Craniopharyngioma has long been a daunting challenge for neurosurgeons and endocrinologists alike. Understanding this complex tumor’s growth mechanism and identifying a potentially effective, non-invasive medication to treat it mark a significant step forward.
“Our ultimate goal is to provide safer and more effective treatment options for patients,” Professor WU said. “This research represents a beacon of hope for improving their quality of life. However, further clinical trials are required to validate the efficacy of amlodipine besylate in patients. ”
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