Abstract 3624: Therapeutic targeting of glioblastoma multiforme using anti-EMP2 antibodies

Abstract

Abstract Despite recent advances in molecular classification, surgery and radiotherapy, and the integration of novel molecular targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In particular, the prognosis for patients with glioblastoma multiforme (GBM), the most common and aggressive form of brain tumors, yields only a median survival of 12 months; the 5-year survival rate of less than 5%. In this report, we show that epithelial membrane protein-2 (EMP2) is a novel tetraspan protein upregulated at both the mRNA and protein levels in 95% of patients with GBM. We have started to characterize the functional consequence of EMP2 up-regulation in GBM cells. Within these cells, EMP2 appears to orchestrate the membrane expression of proteins required for cell migration and invasion. Specifically, our past results as well as our current preliminary results strongly suggest that EMP2 modulates the repertoire of integrin heterodimers on the cell surface and stabilizes the FAK complex and signaling required for cell migration and GBM progression. We further show that this upregulation is sufficient to induce tumor growth in a number of xenograft models using immunocompromised mice. The high expression of EMP2 on the membrane of GBM cells caused us to predict that we could exploit this increase in expression using anti-EMP2 recombinant antibodies. Using both anti-EMP2 antibody fragments (diabodies) as well as a humanized anti-EMP2 IgG1, we show that anti-EMP2 antibodies specifically induce apoptosis both in vitro and in vivo using GBM xenograft models. We have also started characterizing any potential toxicity that may arise from anti-EMP2 therapy. Importantly, no systemic or histological toxicity was observed at therapeutic doses. Thus, we predict that EMP2 expression can be targeted in GBM to develop a novel therapeutic strategy, and it may have broad applicability given that EMP2 expression is upregulated in a number of other tumors such as ovarian and breast cancer. 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 3624. doi:10.1158/1538-7445.AM2011-3624