Abstract LB-273: Inhibition of CD95-dependent signaling for the treatment of glioblastoma multiforme

Abstract

Abstract CD95 (APO-1/FAS) is a receptor that belongs to the Tumor Necrosis Factor Super Family (TNFSF). Binding of the cognate ligand (CD95L) to CD95 triggers intracellular signaling, ultimately leading to apoptotic cell death. Recent research indicates that CD95 depending on the tissue and the conditions also mediates diverse non-apoptotic functions (e.g. liver regeneration, neuronal development, inflammation and cellular migration/invasion of tumor cells). The potential impact on multiple cellular processes classifies the CD95 pathway as an attractive target for pharmacological interference. Apogenix developed APG101 a human fusion protein consisting of the extracellular domain of the CD95 receptor and the Fc-domain of an IgG antibody. APG101 can be used for the treatment of patho-physiological conditions showing an excess of CD95 induced apoptosis (e.g. acute Graft versus Host Disease, [GvHD]) and for malignancies that depend on CD95 regulated cell migration/invasion (e.g. cancer). Comprehensive, preclinical studies have demonstrated the therapeutic potential of APG101 in Glioblastoma Multiforme (GBM) and aGvHD. GBM is a malignant astrocytic tumor that is highly resistant to radiation and chemotherapy induced apoptosis. A major reason for the particular poor prognosis of GBM is the diffuse invasive growth of infiltrating tumor cell into the surrounding brain. These infiltrating tumor cells evade surgery and are a major cause for tumor relapse. For this reason treatment regimens inhibiting the invasive phenotype should be beneficial for the treatment of GBM. It was shown recently that binding of CD95L to its cognate receptor is an important trigger for the invasive growth of glioblastoma cells and that inhibition of CD95 signaling with neutralizing antibodies abolished the invasion of glioblastoma in vitro and in vivo. Data presented here indicate that APG101 is capable to interfere with the invasive phenotype of glioblastoma cell lines in vitro. Furthermore APG101 effectively reduced the migration of invading tumor cells in a syngeneic mouse model of intracranial GBM (SMA-model). In a modified experimental setup the SMA-mouse model was additionally tested for the efficacy of a combinatorial treatment of APG101 and irradiation. These experiments revealed that a combination of APG101 and sub-lethal irradiation inhibits the invasive growth of GBM cells in vivo, whereas radiation alone had no effect on invasive growth. Detailed analysis of the treatment groups indicated that the combination of APG101 and sub-lethal irradiation prevents formation of satellite tumors, an effect that could not be observed in the control groups. Based on the preclinical data set presented, APG101 is currently tested in a clinical Phase II for the treatment of GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-273.