TY - JOUR A1 - Argentiero, Antonella A1 - Solimando, Antonio Giovanni A1 - Krebs, Markus A1 - Leone, Patrizia A1 - Susca, Nicola A1 - Brunetti, Oronzo A1 - Racanelli, Vito A1 - Vacca, Angelo A1 - Silvestris, Nicola T1 - Anti-angiogenesis and immunotherapy: novel paradigms to envision tailored approaches in renal cell-carcinoma JF - Journal of Clinical Medicine N2 - Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintains and reinforces their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy. KW - renal cell carcinoma KW - angiogenesis KW - immune-checkpoint inhibitor KW - tumor microenvironment KW - molecular subtypes KW - prognostic-biomarkers KW - predictive factors Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205846 SN - 2077-0383 VL - 9 IS - 5 ER - TY - JOUR A1 - Rao, Luigia A1 - Giannico, Donato A1 - Leone, Patrizia A1 - Solimando, Antonio Giovanni A1 - Maiorano, Eugenio A1 - Caporusso, Concetta A1 - Duda, Loren A1 - Tamma, Roberto A1 - Mallamaci, Rosanna A1 - Susca, Nicola A1 - Buonavoglia, Alessio A1 - Da Vià, Matteo Claudio A1 - Ribatti, Domenico A1 - De Re, Vallì A1 - Vacca, Angelo A1 - Racanelli, Vito T1 - HB-EGF−EGFR signaling in bone marrow endothelial cells mediates angiogenesis associated with multiple myeloma JF - Cancers N2 - Epidermal growth factor receptor (EGFR) and its ligand heparin-binding EGF-like growth factor (HB-EGF) sustain endothelial cell proliferation and angiogenesis in solid tumors, but little is known about the role of HB-EGF–EGFR signaling in bone marrow angiogenesis and multiple myeloma (MM) progression. We found that bone marrow endothelial cells from patients with MM express high levels of EGFR and HB-EGF, compared with cells from patients with monoclonal gammopathy of undetermined significance, and that overexpressed HB-EGF stimulates EGFR expression in an autocrine loop. We also found that levels of EGFR and HB-EGF parallel MM plasma cell number, and that HB-EGF is a potent inducer of angiogenesis in vitro and in vivo. Moreover, blockade of HB-EGF–EGFR signaling, by an anti-HB-EGF neutralizing antibody or the EGFR inhibitor erlotinib, limited the angiogenic potential of bone marrow endothelial cells and hampered tumor growth in an MM xenograft mouse model. These results identify HB-EGF–EGFR signaling as a potential target of anti-angiogenic therapy, and encourage the clinical investigation of EGFR inhibitors in combination with conventional cytotoxic drugs as a new therapeutic strategy for MM. KW - multiple myeloma KW - HB-EGF KW - EGFR KW - bone marrow angiogenesis KW - endothelial cells Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200786 SN - 2072-6694 VL - 12 IS - 1 ER - TY - JOUR A1 - Krebs, Markus A1 - Solimando, Antonio Giovanni A1 - Kalogirou, Charis A1 - Marquardt, André A1 - Frank, Torsten A1 - Sokolakis, Ioannis A1 - Hatzichristodoulou, Georgios A1 - Kneitz, Susanne A1 - Bargou, Ralf A1 - Kübler, Hubert A1 - Schilling, Bastian A1 - Spahn, Martin A1 - Kneitz, Burkhard T1 - miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro JF - Journal of Clinical Medicine N2 - Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition. KW - microRNA-221 KW - high-risk Prostate Cancer KW - angiogenesis KW - Sunitinib KW - Tyrosine kinase inhibition Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203168 SN - 2077-0383 VL - 9 IS - 3 ER -