A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies
Renal cell carcinoma (RCC) is a kidney cancer with an onset mainly during the sixth or seventh decade of the patient’s life. Patients with advanced, metastasized RCC have a poor prognosis. The majority of patients develop treatment resistance towards Standard of Care (SoC) drugs within months. Tyros...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.889789/full |
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| author | Dennis Gürgen Michael Becker Mathias Dahlmann Susanne Flechsig Elke Schaeffeler Elke Schaeffeler Elke Schaeffeler Florian A. Büttner Christian Schmees Regina Bohnert Jens Bedke Jens Bedke Matthias Schwab Matthias Schwab Matthias Schwab Matthias Schwab Johann J. Wendler Martin Schostak Burkhard Jandrig Wolfgang Walther Wolfgang Walther Wolfgang Walther Jens Hoffmann |
| author_facet | Dennis Gürgen Michael Becker Mathias Dahlmann Susanne Flechsig Elke Schaeffeler Elke Schaeffeler Elke Schaeffeler Florian A. Büttner Christian Schmees Regina Bohnert Jens Bedke Jens Bedke Matthias Schwab Matthias Schwab Matthias Schwab Matthias Schwab Johann J. Wendler Martin Schostak Burkhard Jandrig Wolfgang Walther Wolfgang Walther Wolfgang Walther Jens Hoffmann |
| author_sort | Dennis Gürgen |
| collection | DOAJ |
| description | Renal cell carcinoma (RCC) is a kidney cancer with an onset mainly during the sixth or seventh decade of the patient’s life. Patients with advanced, metastasized RCC have a poor prognosis. The majority of patients develop treatment resistance towards Standard of Care (SoC) drugs within months. Tyrosine kinase inhibitors (TKIs) are the backbone of first-line therapy and have been partnered with an immune checkpoint inhibitor (ICI) recently. Despite the most recent progress, the development of novel therapies targeting acquired TKI resistance mechanisms in advanced and metastatic RCC remains a high medical need. Preclinical models with high translational relevance can significantly support the development of novel personalized therapies. It has been demonstrated that patient-derived xenograft (PDX) models represent an essential tool for the preclinical evaluation of novel targeted therapies and their combinations. In the present project, we established and molecularly characterized a comprehensive panel of subcutaneous RCC PDX models with well-conserved molecular and pathological features over multiple passages. Drug screening towards four SoC drugs targeting the vascular endothelial growth factor (VEGF) and PI3K/mTOR pathway revealed individual and heterogeneous response profiles in those models, very similar to observations in patients. As unique features, our cohort includes PDX models from metastatic disease and multi-tumor regions from one patient, allowing extended studies on intra-tumor heterogeneity (ITH). The PDX models are further used as basis for developing corresponding in vitro cell culture models enabling advanced high-throughput drug screening in a personalized context. PDX models were subjected to next-generation sequencing (NGS). Characterization of cancer-relevant features including driver mutations or cellular processes was performed using mutational and gene expression data in order to identify potential biomarker or treatment targets in RCC. In summary, we report a newly established and molecularly characterized panel of RCC PDX models with high relevance for translational preclinical research. |
| first_indexed | 2024-12-12T08:52:50Z |
| format | Article |
| id | doaj.art-7ac4640177bd4ea9bb1cc13c5cadf092 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-12T08:52:50Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-7ac4640177bd4ea9bb1cc13c5cadf0922022-12-22T00:30:08ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-06-011210.3389/fonc.2022.889789889789A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment StrategiesDennis Gürgen0Michael Becker1Mathias Dahlmann2Susanne Flechsig3Elke Schaeffeler4Elke Schaeffeler5Elke Schaeffeler6Florian A. Büttner7Christian Schmees8Regina Bohnert9Jens Bedke10Jens Bedke11Matthias Schwab12Matthias Schwab13Matthias Schwab14Matthias Schwab15Johann J. Wendler16Martin Schostak17Burkhard Jandrig18Wolfgang Walther19Wolfgang Walther20Wolfgang Walther21Jens Hoffmann22Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Berlin, GermanyExperimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Berlin, GermanyExperimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Berlin, GermanyExperimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Berlin, GermanyDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, GermanyCluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, GermanyGerman Cancer Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, GermanyDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, GermanyNatural and Medical Sciences Institute (NMI) at the University of Tübingen, Reutlingen, GermanyDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, GermanyGerman Cancer Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Urology, University Hospital Tübingen, Tübingen, GermanyDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, GermanyCluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, GermanyGerman Cancer Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartments of Clinical Pharmacology, and Pharmacy and Biochemistry, University of Tübingen, Tübingen, GermanyDepartment of Urology, University Medical Center Magdeburg, Magdeburg, GermanyDepartment of Urology, University Medical Center Magdeburg, Magdeburg, GermanyDepartment of Urology, University Medical Center Magdeburg, Magdeburg, GermanyExperimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Berlin, GermanyExperimental and Clinical Research Center (ECRC) Charité Universitätsmedizin Berlin, Berlin, Germany0Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, GermanyExperimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Berlin, GermanyRenal cell carcinoma (RCC) is a kidney cancer with an onset mainly during the sixth or seventh decade of the patient’s life. Patients with advanced, metastasized RCC have a poor prognosis. The majority of patients develop treatment resistance towards Standard of Care (SoC) drugs within months. Tyrosine kinase inhibitors (TKIs) are the backbone of first-line therapy and have been partnered with an immune checkpoint inhibitor (ICI) recently. Despite the most recent progress, the development of novel therapies targeting acquired TKI resistance mechanisms in advanced and metastatic RCC remains a high medical need. Preclinical models with high translational relevance can significantly support the development of novel personalized therapies. It has been demonstrated that patient-derived xenograft (PDX) models represent an essential tool for the preclinical evaluation of novel targeted therapies and their combinations. In the present project, we established and molecularly characterized a comprehensive panel of subcutaneous RCC PDX models with well-conserved molecular and pathological features over multiple passages. Drug screening towards four SoC drugs targeting the vascular endothelial growth factor (VEGF) and PI3K/mTOR pathway revealed individual and heterogeneous response profiles in those models, very similar to observations in patients. As unique features, our cohort includes PDX models from metastatic disease and multi-tumor regions from one patient, allowing extended studies on intra-tumor heterogeneity (ITH). The PDX models are further used as basis for developing corresponding in vitro cell culture models enabling advanced high-throughput drug screening in a personalized context. PDX models were subjected to next-generation sequencing (NGS). Characterization of cancer-relevant features including driver mutations or cellular processes was performed using mutational and gene expression data in order to identify potential biomarker or treatment targets in RCC. In summary, we report a newly established and molecularly characterized panel of RCC PDX models with high relevance for translational preclinical research.https://www.frontiersin.org/articles/10.3389/fonc.2022.889789/fullkidney cancerrenal cell carcinoma (RCC)clear cell RCCpatient-derived xenograft (PDX)preclinical oncologytargeted therapy |
| spellingShingle | Dennis Gürgen Michael Becker Mathias Dahlmann Susanne Flechsig Elke Schaeffeler Elke Schaeffeler Elke Schaeffeler Florian A. Büttner Christian Schmees Regina Bohnert Jens Bedke Jens Bedke Matthias Schwab Matthias Schwab Matthias Schwab Matthias Schwab Johann J. Wendler Martin Schostak Burkhard Jandrig Wolfgang Walther Wolfgang Walther Wolfgang Walther Jens Hoffmann A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies Frontiers in Oncology kidney cancer renal cell carcinoma (RCC) clear cell RCC patient-derived xenograft (PDX) preclinical oncology targeted therapy |
| title | A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies |
| title_full | A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies |
| title_fullStr | A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies |
| title_full_unstemmed | A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies |
| title_short | A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies |
| title_sort | molecularly characterized preclinical platform of subcutaneous renal cell carcinoma rcc patient derived xenograft models to evaluate novel treatment strategies |
| topic | kidney cancer renal cell carcinoma (RCC) clear cell RCC patient-derived xenograft (PDX) preclinical oncology targeted therapy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.889789/full |
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