The STAT3/TIMP1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from METex14 skipping mutated non-small cell lung cancer: a case report
BackgroundApproximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with brain metastases (BM), which are associated with poor prognosis. Pembrolizumab has shown promising results in advanced NSCLC with PD-L1 ≥ 50%, including patients with BM. Silibinin is a flavonolignan w...
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Frontiers Media S.A.
2025-07-01
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| author | Joaquim Bosch-Barrera Joaquim Bosch-Barrera Joaquim Bosch-Barrera Elia Sais Elia Sais Elia Sais Eduard Teixidor-Vilà Eduard Teixidor-Vilà Carmen Vásquez-Dongo Carmen Vásquez-Dongo Alejandro Hernandez-Martínez Alejandro Hernandez-Martínez Alvaro Romera Alvaro Romera Mel.lina Pinsach-Abuin Bernat del Olmo Glòria Oliveras Emma Polonio-Alcalá Emma Polonio-Alcalá Sara Verdura Sara Verdura Miriam Soriano-Gamero Victor Pineda Hugo Rosales Javier A. Menendez Javier A. Menendez |
| author_facet | Joaquim Bosch-Barrera Joaquim Bosch-Barrera Joaquim Bosch-Barrera Elia Sais Elia Sais Elia Sais Eduard Teixidor-Vilà Eduard Teixidor-Vilà Carmen Vásquez-Dongo Carmen Vásquez-Dongo Alejandro Hernandez-Martínez Alejandro Hernandez-Martínez Alvaro Romera Alvaro Romera Mel.lina Pinsach-Abuin Bernat del Olmo Glòria Oliveras Emma Polonio-Alcalá Emma Polonio-Alcalá Sara Verdura Sara Verdura Miriam Soriano-Gamero Victor Pineda Hugo Rosales Javier A. Menendez Javier A. Menendez |
| author_sort | Joaquim Bosch-Barrera |
| collection | DOAJ |
| description | BackgroundApproximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with brain metastases (BM), which are associated with poor prognosis. Pembrolizumab has shown promising results in advanced NSCLC with PD-L1 ≥ 50%, including patients with BM. Silibinin is a flavonolignan with known blood-brain barrier permeability and anti-BM activity associated with inhibition of the STAT3/TIMP1 signaling axis. To the best of our knowledge, this is the first clinical evidence of combining silibinin with pembrolizumab to achieve a durable partial response in BM, lasting over 9 months.Case ReportWe present the case of a 72-year-old male with stage IVB lung adenocarcinoma and BM, who achieved durable intracranial tumor control with a combination of pembrolizumab and silibinin supplementation. Initial treatment with brain hypofractionated stereotactic radiotherapy and pembrolizumab led to a 14-month partial response. Progression occurred with a new jejunal metastasis and increasing temporal brain lesion. After declining whole-brain radiotherapy, the patient continued pembrolizumab with silibinin (630 mg/day), on a compassionate basis. At 2 months, a partial response in the temporal lobe lesion was observed, and at 9 months, nearly complete intracranial response was achieved with no extracranial progression. Molecular analysis revealed high PD-L1 expression and a METex14, potentially enhancing the response to immunotherapy.ConclusionThis case highlights the potential of silibinin as an adjuvant therapy to enhance anti-PD-1 efficacy in brain metastases, possibly by targeting STAT3/TIMP1-driven immunosuppressive astrocytes. Further investigation of the role of silibinin in improving immunotherapy outcomes in advanced lung cancer patients with BM is required. |
| format | Article |
| id | doaj-art-99b33d4ee3184240a9df9fdb737ba6e8 |
| institution | DOAJ |
| issn | 2296-858X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Medicine |
| spelling | doaj-art-99b33d4ee3184240a9df9fdb737ba6e82025-08-20T03:17:24ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2025-07-011210.3389/fmed.2025.16123271612327The STAT3/TIMP1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from METex14 skipping mutated non-small cell lung cancer: a case reportJoaquim Bosch-Barrera0Joaquim Bosch-Barrera1Joaquim Bosch-Barrera2Elia Sais3Elia Sais4Elia Sais5Eduard Teixidor-Vilà6Eduard Teixidor-Vilà7Carmen Vásquez-Dongo8Carmen Vásquez-Dongo9Alejandro Hernandez-Martínez10Alejandro Hernandez-Martínez11Alvaro Romera12Alvaro Romera13Mel.lina Pinsach-Abuin14Bernat del Olmo15Glòria Oliveras16Emma Polonio-Alcalá17Emma Polonio-Alcalá18Sara Verdura19Sara Verdura20Miriam Soriano-Gamero21Victor Pineda22Hugo Rosales23Javier A. Menendez24Javier A. Menendez25Medical Oncology Department, Catalan Institute of Oncology, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainOncoGIR-PRO (Precision Oncology Group), Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Catalonia, SpainMedical Science Department, School of Medicine, University of Girona, Girona, Catalonia, SpainMedical Oncology Department, Catalan Institute of Oncology, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainOncoGIR-PRO (Precision Oncology Group), Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Catalonia, SpainMedical Science Department, School of Medicine, University of Girona, Girona, Catalonia, SpainMedical Oncology Department, Catalan Institute of Oncology, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainOncoGIR-PRO (Precision Oncology Group), Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Catalonia, SpainMedical Science Department, School of Medicine, University of Girona, Girona, Catalonia, SpainDepartment of Pathology, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainMedical Oncology Department, Catalan Institute of Oncology, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainOncoGIR-PRO (Precision Oncology Group), Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Catalonia, SpainMedical Oncology Department, Catalan Institute of Oncology, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainOncoGIR-PRO (Precision Oncology Group), Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Catalonia, SpainMolecular Diagnostics and Precision Medicine Unit, Girona Territorial Clinical Laboratory, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainMolecular Diagnostics and Precision Medicine Unit, Girona Territorial Clinical Laboratory, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainDepartment of Pathology, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainOncoGIR-PRO (Precision Oncology Group), Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Catalonia, SpainMedical Science Department, School of Medicine, University of Girona, Girona, Catalonia, SpainProgram Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Girona, Catalonia, SpainMetabolism & Cancer Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, SpainOncoGIR-PRO (Precision Oncology Group), Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Catalonia, SpainDepartment of Radiology, Diagnostic Imaging Institute, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainDepartment of Radiotherapy, Catalan Institute of Oncology, Dr. Josep Trueta University Hospital, Girona, Catalonia, SpainProgram Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Girona, Catalonia, SpainMetabolism & Cancer Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, SpainBackgroundApproximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with brain metastases (BM), which are associated with poor prognosis. Pembrolizumab has shown promising results in advanced NSCLC with PD-L1 ≥ 50%, including patients with BM. Silibinin is a flavonolignan with known blood-brain barrier permeability and anti-BM activity associated with inhibition of the STAT3/TIMP1 signaling axis. To the best of our knowledge, this is the first clinical evidence of combining silibinin with pembrolizumab to achieve a durable partial response in BM, lasting over 9 months.Case ReportWe present the case of a 72-year-old male with stage IVB lung adenocarcinoma and BM, who achieved durable intracranial tumor control with a combination of pembrolizumab and silibinin supplementation. Initial treatment with brain hypofractionated stereotactic radiotherapy and pembrolizumab led to a 14-month partial response. Progression occurred with a new jejunal metastasis and increasing temporal brain lesion. After declining whole-brain radiotherapy, the patient continued pembrolizumab with silibinin (630 mg/day), on a compassionate basis. At 2 months, a partial response in the temporal lobe lesion was observed, and at 9 months, nearly complete intracranial response was achieved with no extracranial progression. Molecular analysis revealed high PD-L1 expression and a METex14, potentially enhancing the response to immunotherapy.ConclusionThis case highlights the potential of silibinin as an adjuvant therapy to enhance anti-PD-1 efficacy in brain metastases, possibly by targeting STAT3/TIMP1-driven immunosuppressive astrocytes. Further investigation of the role of silibinin in improving immunotherapy outcomes in advanced lung cancer patients with BM is required.https://www.frontiersin.org/articles/10.3389/fmed.2025.1612327/fullsilymarinimmunotherapynatural productlung adenocarcinomabrain radiotherapy |
| spellingShingle | Joaquim Bosch-Barrera Joaquim Bosch-Barrera Joaquim Bosch-Barrera Elia Sais Elia Sais Elia Sais Eduard Teixidor-Vilà Eduard Teixidor-Vilà Carmen Vásquez-Dongo Carmen Vásquez-Dongo Alejandro Hernandez-Martínez Alejandro Hernandez-Martínez Alvaro Romera Alvaro Romera Mel.lina Pinsach-Abuin Bernat del Olmo Glòria Oliveras Emma Polonio-Alcalá Emma Polonio-Alcalá Sara Verdura Sara Verdura Miriam Soriano-Gamero Victor Pineda Hugo Rosales Javier A. Menendez Javier A. Menendez The STAT3/TIMP1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from METex14 skipping mutated non-small cell lung cancer: a case report Frontiers in Medicine silymarin immunotherapy natural product lung adenocarcinoma brain radiotherapy |
| title | The STAT3/TIMP1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from METex14 skipping mutated non-small cell lung cancer: a case report |
| title_full | The STAT3/TIMP1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from METex14 skipping mutated non-small cell lung cancer: a case report |
| title_fullStr | The STAT3/TIMP1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from METex14 skipping mutated non-small cell lung cancer: a case report |
| title_full_unstemmed | The STAT3/TIMP1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from METex14 skipping mutated non-small cell lung cancer: a case report |
| title_short | The STAT3/TIMP1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from METex14 skipping mutated non-small cell lung cancer: a case report |
| title_sort | stat3 timp1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from metex14 skipping mutated non small cell lung cancer a case report |
| topic | silymarin immunotherapy natural product lung adenocarcinoma brain radiotherapy |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2025.1612327/full |
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