Therapeutic Effects of Inhibition of Sphingosine-1-Phosphate Signaling in HIF-2α Inhibitor-Resistant Clear Cell Renal Cell Carcinoma.

Autor:	Hoefflin R; Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Harlander S; Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland.; Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland., Abhari BA; Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Peighambari A; Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Adlesic M; Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland., Seidel P; Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Zodel K; Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Haug S; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany., Göcmen B; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany., Li Y; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany., Lahrmann B; Steinbeis Transfer Center for Medical Systems Biology, 69120 Heidelberg, Germany., Grabe N; Steinbeis Transfer Center for Medical Systems Biology, 69120 Heidelberg, Germany.; Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany.; National Center of Tumor Diseases, Medical Oncology, University Hospital Heidelberg, 69121 Heidelberg, Germany., Heide D; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Boerries M; Institute of Medical Bioinformatics and Systems Medicine, Medical Centre, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; German Cancer Consortium (DKTK), Partner Site Freiburg, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Köttgen A; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany., Heikenwalder M; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Frew IJ; Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland.; Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland.; German Cancer Consortium (DKTK), Partner Site Freiburg, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79106 Freiburg, Germany.
Jazyk:	angličtina
Zdroj:	Cancers [Cancers (Basel)] 2021 Sep 25; Vol. 13 (19). Date of Electronic Publication: 2021 Sep 25.
DOI:	10.3390/cancers13194801
Abstrakt:	Specific inhibitors of HIF-2α have recently been approved for the treatment of ccRCC in VHL disease patients and have shown encouraging results in clinical trials for metastatic sporadic ccRCC. However, not all patients respond to therapy and pre-clinical and clinical studies indicate that intrinsic as well as acquired resistance mechanisms to HIF-2α inhibitors are likely to represent upcoming clinical challenges. It would be desirable to have additional therapeutic options for the treatment of HIF-2α inhibitor resistant ccRCCs. Here we investigated the effects on tumor growth and on the tumor microenvironment of three different direct and indirect HIF-α inhibitors, namely the HIF-2α-specific inhibitor PT2399, the dual HIF-1α/HIF-2α inhibitor Acriflavine, and the S1P signaling pathway inhibitor FTY720, in the autochthonous Vhl/Trp53/Rb1 mutant ccRCC mouse model and validated these findings in human ccRCC cell culture models. We show that FTY720 and Acriflavine exhibit therapeutic activity in several different settings of HIF-2α inhibitor resistance. We also identify that HIF-2α inhibition strongly suppresses T cell activation in ccRCC. These findings suggest prioritization of sphingosine pathway inhibitors for clinical testing in ccRCC patients and also suggest that HIF-2α inhibitors may inhibit anti-tumor immunity and might therefore be contraindicated for combination therapies with immune checkpoint inhibitors.
Databáze:	MEDLINE
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