PATH-14. ALPHA CARDIAC ACTIN EXPRESSION IS OBSERVED IN AGGRESSIVE GLIOMA SUBTYPES AND GLIOBLASTOMA STEM CELLS

BACKGROUND Alterations in actin subunit expression have previously been observed in multiple cancers. In glioblastoma (GBM), the expression of ACTC1 has been associated with a more invasive phenotype and with shorter survival. We sought to explore the diversity of actin subunit expression across glioma subtypes and patient derived glioblastoma stem cells (GSCs). METHODS Bioinformatic analysis of multiple glioma databases was performed to profile actin subunit (ACTA1, ACTA2, ACTC1, ACTG1, ACTG2, and ACTB) mRNA levels. Expression levels were also evaluated in normal brain in comparison to liver and heart tissue. Western blot was used to analyze protein expression in GSCs, surgical tissue and human fetal astrocytes. RESULTS The primary actin subunits expressed in normal brain are beta actin (ACTB) and gamma actin (ACTG1). RNA sequencing of tissue from multiple glioma subtypes or different brain regions reveals a global increase in ACTG1 and ACTB abundance in gliomas compared to normal brain. LGG-GCIMP high and LGG-co-deleted glioma subtypes have the lowest ACTC1 expression. LGG-GCIMP low (HR 9.75, P< 0.001), LGG-mesenchymal-like (HR11.1, P< 0.001), LGG-classic-like (HR10.96, P< 0.001) subtypes are associated with ACTC1 expression. ACTC1, ACTCB, and ACTG protein expression was observed in GSCs, freshly resected GBM tissue, and human fetal astrocytes. CONCLUSIONS Gliomas have a specific pattern of actin subunit expression that differs in actin subunit type and abundance when compared to normal adult brain. Expression of ACTC1 is found in aggressive glioma subtypes and is shared by GSCs and human fetal astrocytes. Investigation into the neurodevelopmental role of ACTC1 and its contribution to oncogenic transformation in GBM is warranted.

A Pilot Study of Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma

High-grade gliomas (HGGs) carry a dismal prognosis despite current treatments. We previously confirmed the safety and immunogenicity of a vaccine treatment targeting tumor angiogenesis with synthetic peptides, for vascular endothelial growth factor receptor (VEGFR) epitopes in recurrent HGG patients. In this study, we evaluated a novel vaccine therapy targeting not only tumor vasculature but also tumor cells, using multiple glioma oncoantigen (GOA)/glioma angiogenesis-associated antigen (GAAA) peptides in HLA-A2402+ recurrent/progressive HGG patients. The vaccine included peptide epitopes from four GOAs (LY6K, DEPDC1, KIF20A, and FOXM1) and two GAAAs (VEGFR1 and VEGFR2). Ten patients received subcutaneous vaccinations. The primary endpoint was the safety of the treatment. T-lymphocyte responses against GOA/GAAA epitopes and treatment response were evaluated secondarily. The treatment was well tolerated without any severe systemic adverse events. The vaccinations induced immunoreactivity to at least three vaccine-targeted GOA/GAAA in all six evaluable patients. The median overall survival time in all patients was 9.2 months. Five achieved progression-free status lasting at least six months. Two recurrent glioblastoma patients demonstrated stable disease. One patient with anaplastic oligoastrocytoma achieved complete response nine months after the vaccination. Taken together, this regimen was well tolerated and induced robust GOA/GAAA-specific T-lymphocyte responses in recurrent/progressive HGG patients.