Abstract
BACKGROUND: Although successful treatment of papillary craniopharyngiomas (PCPs) with BRAFv600e inhibitors has been reported in clinical trials, studies have shown that approximately 10% of PCPs lack the BRAFv600e mutation and that BRAFv600e inhibitors may not be significantly effective against these tumors. However, no studies have focused specifically on BRAFv600e(-) PCPs. METHODS: Spatial transcriptome sequencing was performed on calcified PCP tissue to identify novel subtypes of PCP cells. The findings were validated via pathological methods in 51 PCP samples. Primary PCP cells from BRAFv600e(-) PCP patients and BRAFv600e(+) PCP patients were isolated and then injected into the brains of nude mice via stereotactic surgery to establish a stable mouse model of human-originated PCP. Model mice were treated with vemurafenib, a BRAF inhibitor, and anlotinib, an angiogenesis inhibitor. BRAFv600e(-)PCP patients were treated with anlotinib in a phase 1 clinical trial. Changes in the tumors of the model mice and patients were monitored via pathological methods, CT and MRI. RESULTS: Most of calcified PCPs were negative for the BRAFv600e mutation, and findings from the mouse model confirmed that vemurafenib may not have a significant therapeutic effect on BRAFv600e(-) PCPs. However, the mouse model verified that, anlotinib may have a significant therapeutic effect on BRAFv600e(-) PCPs. Two patients with BRAFv600e(-) PCPs participated in a phase 1 clinical trial and received anlotinib therapy; their tumors disappeared after 3 months of therapy and did not recur within 24 months follow-up after stopping the treatment. CONCLUSION: BRAFv600e(-) PCPs are characterized by calcification and do not respond to the BRAF inhibitor vemurafenib, and for which the angiogenesis inhibitor anlotinib may have a significant therapeutic effect.