Artikel
Organoid models for the prediction of therapy response on tyrosine kinase inhibitors in clear cell renal cell carcinoma
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Autoren
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Katharina Baschun
- Universitätsklinikum Bonn, Institut für Pathologie, Bonn, Deutschland
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L. K. Esser
- Universitätsklinikum Bonn, Institut für Pathologie, Bonn, Deutschland
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K. Fuchs
- Universitätsklinikum Bonn, Institut für Pathologie, Bonn, Deutschland
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A. Sahu
- Universitätsklinikum Bonn, Core Unit of Bioinformatics Analyses, Bonn, Germany
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Niklas Klümper
- Universitätsklinikum Bonn, Institut für Urologie, Bonn, Deutschland
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A. Buness
- Universitätsklinikum Bonn, Core Unit of Bioinformatics Analyses, Bonn, Germany
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Jörg Ellinger
- Universitätsklinikum Bonn, Institut für Urologie, Bonn, Deutschland
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Manuel Ritter
- Universitätsklinikum Bonn, Institut für Urologie, Bonn, Deutschland
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G. Kristiansen
- Universitätsklinikum Bonn, Institut für Pathologie, Bonn, Deutschland
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M. Hölzel
- Universitätsklinikum Bonn, Institute of Experimental Oncology, Bonn, Germany
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M. I. Toma
- Universitätsklinikum Bonn, Institut für Pathologie, Bonn, Deutschland
| Veröffentlicht: | 26. März 2024 |
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Gliederung
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Introduction: Renal cancer is one of the most common neoplasms of the urinary tract system, making up 96% of the malignant neoplasia of the kidney. Clear cell renal cell carcinoma is the most common subtype, with a metastasis risk of about 30–50%. The first line therapy of metastasized RCC comprise combinations of immunecheckpoint inhibitors and tyrosine kinase inhibitors depending on the patient’s risk profile. The aim of this study was to predict the therapy response to TKI in organoid models.
Material and methods: 32 patients undergoing a partial or radial nephrectomy between 2019 and 2020 at the Department of Urology, University Hospital Bonn, were included. We cultivated Air-Liquid Interface Patient Derived Organoids (ALI PDOs) from fresh tumor material. The organoids were treated with 25 µM/ml Cabozantinib for one or three weeks, while the control group remained untreated. We determined therapy response by quantifying necrotic areas after embedding the organoids. Bulk RNA 3’ Seq of our primary tissues was performed and the results were correlated with the therapy response. Promising markers were stained by immunohistochemistry.
Results: We successfully cultivated 24 cases. All cases were treated for one week and 16 cases also for three weeks with Cabozantinib. A high therapy response (more than 66% necrotic areas) was noticed in 41.7% after one week of treatment and 56.2% after three weeks of treatment. RNA Seq revealed TNFRSF12A is significantly upregulated and SEMA3D is significantly downregulated in the cohort with a good therapy response. The survival analysis of the TCGA Kidney renal clear cell carcinoma (TCGA-KIRC) cohort revealed that the upregulation of TNFRSF12A and downregulation of SEMA3D is significantly correlated with shorter survival times in renal cancer.
Conclusion: Organoids are a promising tool for therapy testing in vitro and identification of predictive biomarkers, which could potentially improve the therapy choices in renal cancer.
