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Anlotinib may have a therapeutic effect on papillary craniopharyngiomas without the BRAFv600e mutation
Yilamujiang Ainiwan1, Haomin Li1,2, Yongjia Zheng3
1Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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.
Insights
Papillary craniopharyngiomas (PCPs) lacking the BRAFv600e mutation are calcified and resistant to vemurafenib. The angiogenesis inhibitor anlotinib shows significant therapeutic potential for these BRAFv600e-negative PCPs.
Area of Science:
- Neuro-oncology
- Molecular pathology
- Translational medicine
Background:
- Papillary craniopharyngiomas (PCPs) are a subtype of craniopharyngioma.
- BRAFv600e inhibitors are effective for some PCPs, but not all.
- BRAFv600e-negative (BRAFv600e-) PCPs represent a distinct subset with unknown therapeutic vulnerabilities.
Purpose of the Study:
- To investigate the characteristics and therapeutic strategies for BRAFv600e-negative PCPs.
- To identify novel therapeutic targets beyond BRAFv600e inhibition in PCPs.
Main Methods:
- Spatial transcriptome sequencing of calcified PCP tissue to identify cell subtypes.
- Validation in 51 PCP samples.
- Establishment of BRAFv600e- and BRAFv600e+ PCP mouse models.
- Treatment of mouse models with vemurafenib (BRAF inhibitor) and anlotinib (angiogenesis inhibitor).
- Phase 1 clinical trial of anlotinib in BRAFv600e- PCP patients.
Main Results:
- Most calcified PCPs were BRAFv600e-.
- BRAFv600e- PCPs showed resistance to vemurafenib in mouse models.
- Anlotinib demonstrated significant therapeutic effects in BRAFv600e- PCP mouse models.
- Two BRAFv600e- PCP patients treated with anlotinib achieved complete tumor remission, with no recurrence during 24 months follow-up.
Conclusions:
- BRAFv600e- PCPs are characterized by calcification and lack of response to BRAF inhibitors.
- The angiogenesis inhibitor anlotinib shows promising therapeutic efficacy for BRAFv600e- PCPs.
- Anlotinib represents a potential targeted therapy for this specific subset of craniopharyngiomas.
