Abstract 1220: ErbB4: A novel therapeutic target in glioblastoma multiforme

Abstract

Abstract Introduction: Glioblastoma Multiforme or glioma is amongst the most lethal and difficult to cancers to treat and kills 1,000 Australians and 12,000 Americans every year. The average age at diagnosis is 60 years and the death rate for glioma has remained relatively unchanged for the past 20 years; highlighting the need for new therapeutic options for its treatment. ErbB4, the fourth member of the EGFR family has both oncogenic and tumor suppressive activity dependent upon isoform expression and although ErbB4 is universally expressed in glioma, its functional role is somewhat unclear. Aims: The aim of this study was to characterize the expression of ErbB4 in a large cohort of glioma tissues at the protein and mRNA level and determine if ErbB4 expression relates to tumor biology and patient survival. Methods: Immunohistochemistry was performed on paraffin sections of glioma tissue (n=68) and normal brain (n=5) for the immunolocalisation of ErbB4 and EGFR (total and activated) and the ErbB4 ligand heregulin. Using a customized RT-qPCR assay, ErbB4 isoforms were identified in snap frozen glioma (n=23) and normal brain (n=15). Results: Patients diagnosed with glioma (n=68) had a median survival time of 15 months (range 1-120 months) with the average age of 63±2 years (range 21-80 years). ErbB4 and heregulin protein was demonstrated in all our glioma and normal brain samples. At the mRNA level however, ErbB4 expression was reduced in the glioma samples when compared to normal brain tissue. All six ErbB4 isoforms were demonstrated in all tissue samples and ErbB4 was preferentially expressed as the JMa/Cyt2 isoform in glioma. Histologically, ErbB4 activation (independent of EGFR activation) occurred in 16% of patient samples and was localized to sites like the leading edge of the tumor. The mean survival time for patients with high levels of activated ErbB4 was 12 months, while patients with low levels of activated ErbB4 had a mean survival time of 32 months. ErbB4, activated ErbB4 and heregulin were also demonstrated in the vasculature of the glioma but not normal brain. Conclusions: This study demonstrated the preferential expression of the JMa/Cyt-2 isoform of ErbB4 in glioma along with increased ErbB4 activation significantly shortening patient survival times. Due to a potential angiogenic role of ErbB4 in glioma and reduced patient survival times following ErbB4 activation, ErbB4 should be considered a new therapeutic target in glioma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1220. doi:1538-7445.AM2012-1220