TY - JOUR A1 - Marquardt, André A1 - Hartrampf, Philipp A1 - Kollmannsberger, Philip A1 - Solimando, Antonio G. A1 - Meierjohann, Svenja A1 - Kübler, Hubert A1 - Bargou, Ralf A1 - Schilling, Bastian A1 - Serfling, Sebastian E. A1 - Buck, Andreas A1 - Werner, Rudolf A. A1 - Lapa, Constantin A1 - Krebs, Markus T1 - Predicting microenvironment in CXCR4- and FAP-positive solid tumors — a pan-cancer machine learning workflow for theranostic target structures JF - Cancers N2 - (1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database — representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets. KW - machine learning KW - tumor microenvironment KW - immune infiltration KW - angiogenesis KW - mRNA KW - miRNA KW - transcriptome Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305036 SN - 2072-6694 VL - 15 IS - 2 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 - TY - THES A1 - Partzsch, Bernhard T1 - Identifizierung und Isolierung von Angiostatin aus dem Urin bei Patienten mit Prostatakarzinom T1 - Identification and isolation of angiostatin in the urine of patients with prostate cancer N2 - Die Angiogenese beschreibt einen entscheidenden Schritt für Tumorwachstum und Metastasierung. Die Tendenz, neue Blutgefäße zu bilden, wird durch das Gleichgewicht angiogener und nicht-angiogener Faktoren bestimmt. In einer Reihe eleganter tierexperimenteller Versuche gelang es O`Reilly erstmals einen tumorassoziierten Inhibitor der Angiogenese, den er Angiostatin nannte, nachzuweisen und zu isolieren. Uns gelang es, im Western-Blot Angiostatin und Angiostatin-Spaltprodukte sowohl aus dem Urin von PCa-Patienten als auch aus dem Urin gesunder Probanden nachzuweisen und zu isolieren. Die anti-angiogene Wirksamkeit des von uns isolierten Proteins wurde im Endothelzellkultur-Assay bestätigt. Eine Differenzierung gesunder Personen von PCa-Patienten war aufgrund der kleinen Fallzahlen nicht möglich. Der Nachweis von Angiostatin bei Gesunden belegt aber, dass anti-angiogene Proteine unabhängig vom Vorhandensein maligner Tumore im Urin ausgeschieden werden. Es bleibt zu vermuten, dass Angiogenese-Inhibitoren ähnlich den Gerinnungsfaktoren bei Bedarf aktiviert und inaktiviert werden können. Der Angiogenese zugrunde liegende Mechanismen und beteiligte Faktoren sind Bestandteil intensiver Forschung. Unklar ist, ob Angiogenese-Inhibitoren in Zukunft in der Krebstherapie die Rolle spielen werden, die man ihnen bei ihrer Entdeckung zuschrieb. N2 - Angiogenesis is an essential component for tumor growth and metastasis. The formation of new blood vessels is controlled by the balance of angiogenic and angiogenesis-inhibiting factors. In several animal experiments O`Reilly was able to isolate a tumorassociated inhibitor of angiogenesis, which was named angiostatin. We ware able to detect angiostatin and angiostatin fragments in the Western blot analysis as well in the urine of patients with prostate cancer as in the urine of healthy persons. The anti-angiogenic function of the isolated protein was confirmed in an endothelial proliferation assay.Because of the small number of cases it was not possible to differentiate between healthy people and patients with prostate cancer. The detection of angiostatin in the urine of healthy persons shows, that antiangiogenic proteins are excreted with the urine even if there is no tumor. It might be possible, that inhibitors of angiogenesis – similar to the factors of the coagulation system – could be activated and inactivated if required. The mechanism of angiogenesis and the included factors are part of an intensive research. It is not clear yet, whether inhibitors of angiogenesis would be that important for therapy of tumors, that they were guessed to be when they were discovered. KW - Angiogenese KW - Angiostatin KW - Prostatakarzinom KW - Urin KW - angiogenesis KW - angiostatin KW - prostate cancer KW - urine Y1 - 2004 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-17814 ER - 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 -