Seit 60 Jahren setzt sich die Saarländische Krebsgesellschaft für an Krebs erkrankte Menschen und deren Angehörige im Saarland ein und jeder Tag zeigt, wie umfassende Informationen, einfühlsame Beratung und konkrete Schritte wirklich helfen können, die Diagnose anzunehmen, mit der Erkrankung zu leben, Ängste zu überwinden und neue Hoffnung zu schöpfen. Die Diagnose „Krebs“ verändert den normalen Alltag. Ängste und Unsicherheiten belasten die Betroffenen und ihr Umfeld. Angehörige fühlen sich überfordert, Freunde und Bekannte sind verunsichert. Krebskranke Menschen benötigen über die medizinische Hilfe hinaus häufig Unterstützung bei der Bewältigung von psychischen und sozialen Belastungen. Die Jubiläumsfeier findet am Samstag, 20. Oktober, ab 10.00 Uhr im Festsaal im Schloss Saarbrücken statt. Nachmittags wird in diesem Rahmen ein Patienteninformationstag mit Vorträgen von Onkologen und Ärzten stattfinden.

Glioblastoma multiforme (GBM) is the most malignant brain tumor. Integrin-mediated tumor-stroma-interactions and EGFR-signaling are crucial for proliferation, invasion and angiogenesis in GBM. Cilengitide (inhibits αvβ3 and αvβ5 integrin signaling) and cetuximab (binds to EGFR inhibiting auto-phosphorylation and downstream signaling) have shown beneficial effects on GBM in preclinical studies with radiation therapy in dual combinations and clinical phase II and III trials are ongoing. Since gliomagenesis is controlled by numerous components including EGFR and αvβ3 and αvβ5 integrins, we hypothesized that the triple combination of cilengitide, cetuximab and radiation had beneficial combinatory effects. The effects of this combination were assessed in vitro and in vivo in an orthotopic glioma model in mice. In vitro, we used U87 glioma cells and primary human endothelial cells (EC). We determined the effects of cilengitide, cetuximab and radiation and their combinations on proliferation, clonogenic survival and migration. For our in vivo studies, primary human glioblastoma cancer-stem-cell-like cells (CSCLs) were subcultured as neurospheres and stereotactically implanted into brains of mice. Mice were treated with cetuximab, cilengitide, radiation (7 Gy single dose) and their combinations. The treatment effects were assessed with MRI, histology and survival time evaluation. In vitro, both drugs reduced clonogenicity, proliferation and migration ability of U87 and EC which was enhanced by radiation and triple combination demonstrating the strongest effects. In the orthotopic model all monotherapies induced tumor growth delay and prolonged survival which was significantly enhanced by combination treatments. Triple therapy showed the best outcome with respect to tumor growth delay and mouse survival. Histology showed that cilengitide and cetuximab markedly reduced the constitutional and radiation-related parenchymal invasion. On IHC we found that monotherapies reduced the glioma proliferation index (KI67) and micro vessel density (CD31) which was enhanced by their combination. Triple therapy showed the strongest antiproliferative and antiangiogenic effect. The combination of cilengitide, cetuximab and radiation shows remarkable anti-tumorigenic and especially anti-invasive and anti-angiogenic effects in vitro and in an orthotopic glioma model. The concurrent inhibition of integrin and EGFR signaling may both enhance the direct antitumor effects of radiation therapy and at the same time effectively attenuate radiation evoked tumor escape mechanisms. Our results indicate that this triple combination of targeted drugs which are readily available with radiation therapy is a promising approach for clinical studies in human GBM.

Abstract Objective: Despite progress in understanding molecular changes in glioblastoma multiforme (GBM), it remains a cancer with poor prognosis in need of better therapy. Pathological features of GBM are explosive growth, angiogenesis and its unique diffuse, infiltrative growth pattern. There is a consensus that cell-matrix-interactions play a pivotal role for infiltrative growth. Connective tissue growth factor (CTGF) is a matricellular protein that is involved in many pathological processes including tumorigenesis and invasion. CTGF modulates cell-matrix-interactions that may allow glioma cells to invade brain parenchyma, degrade the extracellular matrix (ECM), and enhance proliferation and angiogenesis in GBM. High CTGF-expression levels have been reported to correlate with tumor grade, invasiveness and poor patient survival. Here the effects of a human monoclonal anti-CTGF-antibody (FG-3019) were investigated alone and in combination with irradiation in vitro and in vivo in an orthotopic glioma model in mice. Methods and materials: In vitro studies were performed with two established human glioma cell lines, U87MG and T98G, as well as with primary isolated human glioblastoma cancer stem-like cells (CSLCs) cells. The effects of FG-3019 alone and in combination with photon irradiation (6 MV Linac) on clonogenic survival, proliferation, migration, neurosphere formation, and limiting dilution were determined. RNA was isolated from CSLCs and gene expression changes were examined after different treatments using micro-arrays and RT-PCR. In vivo, CSLCs were subcultured as neurospheres and stereotactically implanted into brains of SCID-beige mice. Mice brains were treated with 7Gy single dose radiation +/− FG-3019. The treatment effects were assessed by MRI, survival time and histology. Results: Tumor growth delay in the orthotopic tumor model resulted from treatment with radiation or FG-3019 alone, which was significantly enhanced by combined treatment. Similarly, animal survival was prolonged by each monotherapy and significantly enhanced by the combination. Histology showed that FG-3019 significantly reduced constitutive and radiation-induced tumor invasion into the brain parenchyma. FG-3019 also reduced intracellular CTGF expression, glioma cell proliferation, deposition of different types of collagen and reduced microvessel density. FG-3019 also reduced expression of Nestin and the stem cell marker SOX-2. In vitro, FG-3019 and irradiation reduced clonogenicity, proliferation and migration of U87MG, T98G and CSLCs, which was enhanced by the combination. Gene expression analysis revealed that FG-3019 down regulated tumorigenesis- and tumor-invasion-related genes. Conclusions: The human monoclonal CTGF antibody, FG-3019, shows remarkable anti-tumorigenic and anti-invasive effects in vitro and in vivo in a primary human glioblastoma model growing orthotopically in mice. Our results indicate that FG-3019 alone and in combination with radiotherapy is a promising approach for clinical translation in humans. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B206.