Abstract
Despite the numerous available drugs, the most appropriate treatments for patients affected by common or rare renal cell carcinomas (RCC), like those associated with the Xp11.2 translocation/transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) gene fusion (TFE3 RCC), are not clearly defined. We aimed to make a parallel between the sensitivity to targeted therapies on living patients and on cells derived from the initial tumor. Three patients diagnosed with a metastatic RCC (one clear cell RCC [ccRCC], two TFE3 RCC) were treated with anti-angiogenesis drugs. The concentrations of the different drugs giving 50% inhibition of cell proliferation (IC50) were determined with the Thiazolyl Blue Tetrazolium Bromide (MTT) assay on cells from the primary tumors and a reference sensitive RCC cell line (786-O). We considered the cells to be sensitive if the IC50 was lower or equal to that in 786-O cells, and insensitive if the IC50 was higher to that in 786-O cells (IC 50 of 6 ± 1 µM for sunitinib, 10 ± 1 µM for everolimus and 6 ± 1 µM for sorafenib). Based on this standard, the response in patients and in cells was equivalent. The efficacy of anti-angiogenesis therapies was also tested in cells obtained from five patients with non-metastatic ccRCC, and untreated as recommended by clinical practice in order to determine the best treatment in case of progression toward a metastatic grade. In vitro experiments may represent a method for evaluating the best first-line treatment for personalized management of ccRCC during the period following surgery.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Antineoplastic Agents / pharmacology*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Carcinoma, Renal Cell / drug therapy
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / pathology*
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Disease Models, Animal
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Drug Resistance, Neoplasm
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Female
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Gene Expression
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Humans
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Indoles / pharmacology
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Kidney Neoplasms / drug therapy
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Kidney Neoplasms / pathology*
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Mice
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Molecular Targeted Therapy
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Neoplasm Metastasis
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Neoplasm Staging
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism
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Niacinamide / analogs & derivatives
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Niacinamide / pharmacology
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Phenylurea Compounds / pharmacology
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Precision Medicine
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Pyrroles / pharmacology
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Sorafenib
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Sunitinib
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Antineoplastic Agents
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Indoles
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Phenylurea Compounds
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Pyrroles
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TFE3 protein, human
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Niacinamide
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Sorafenib
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Receptor Protein-Tyrosine Kinases
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Sunitinib
Supplementary concepts
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Clear-cell metastatic renal cell carcinoma
Grants and funding
This work was supported by institutional national fundings for research («the Institut National pour la Santé et la Recherche Médicale», the «Centre National de la Recherche Scientifique», the «Centre Scientifique de Monaco», the National Institute of Cancer) and charities (the Association for Cancer Research, the «Fondation de France», the «Fondation pour la Recherche Médicale», The «Association pour la Recherche sur les Tumeurs du Rein»). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.