Abstract LB-382: Inhibition of CD95 signalling by APG-101 enhances efficacy of radiotherapy (RT) and reduces RT-induced tumor satellite formation

Abstract

Abstract CD95 is a prototype death receptor that regulates the induction of apoptosis, upon binding of its ligand CD95L. Therefore, activation of the CD95L/CD95 system has been regarded an excellent target for treatment of various malignancies. In contrast to the aim of promoting CD95 activation, there is compelling evidence that CD95 is able to promote tumor growth through intracellular non-apoptotic signalling mechanisms. This mechanism has recently been described for glioblastoma, in which activation of CD95 by CD95L leads to invasive growth and glioma cell migration. This is signalled through increased activity of pivotal glioblastoma invasion-related proteases, that is matrix metalloproteinases (MMP). With this shift of paradigms, blocking of the CD95L mediated invasion of tumor cells and subsequent tumor progression may therefore be a promising approach in anti-glioma therapy. APG101 is a fusion protein, consisting of the extracellular domain of human CD95 and the Fc-region of human immunoglobulin G. Hence, it acts as a soluble CD95 receptor trapping the CD95 ligand. The presented project aims at analyzing the clinical relevance of blocking CD95 signalling, given the fact that glioma patients with upregulated CD95 expression have worse survival rates than those with intermediate expression levels. In proof-of principle experiments APG101 inhibits CD95L-mediated invasion of glioma cells. More importantly, APG101-treatment (100 mg/kg body weight) resulted in significantly prolonged survival of SMA560-tumor bearing Vm/Dk mice, less glioma cell satellites in the surrounding tissue and reduced activity of MMP. APG101 in combination with focal irradiation at 6 Gy demonstrated a remarkable reduction of tumor growth with a significantly prolonged survival compared with irradiation treatment alone and inhibition of the proinvasive properties of radiotherapy as demonstrated by magnetic resonance imaging and histology. Surprisingly, APG-101 added to the vascular endothelial growth factor receptor (VEGFR) inhibitor cediranib (AZD2171) did not increase the survival of SMA-560-tumor bearing mice as compared to cediranib alone nor did it impair the proinvasive consequences of cediranib. Our data strongly support the potential use and clinical evaluation of APG101 in combination with radiotherapy in the treatment of malignant glioma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-382. doi:10.1158/1538-7445.AM2011-LB-382