TMOD-04. T-TYPE CALCIUM CHANNELS DRIVE GLIOBLASTOMA INITIATION AND PROGRESSION

Abstract

Abstract Glioblastoma is the most common primary malignant brain tumor with a dismal median survival of 15 months. Calcium signaling regulates a plethora of cellular processes making it an ideal target for therapeutic intervention. Our group identified T-type calcium channels (TTCCs) as upregulated in GBM cells, stem cells and human tumors. Analysis of the Cancer Genome Atlas (TCGA) demonstrates for the first time that >20% of GBM patients exhibit mutation, amplification or mRNA upregulation of TTCCs. TCGA and Chinese Glioma Genome Atlas (CGGA) data analyses demonstrate that patients with alterations in TTCC trend toward worse survival compared to normal TTCC expression. Our group utilized an FDA repurposed TTCC blocker Mibefradil to demonstrate inhibition of TTCCs decreases cancer associated signaling, transcription, malignancy parameters and in vivo tumor growth. Mibefradil treatment sensitized Gliomas stem like cells (GSC) xenografts to temozolomide (TMZ) chemotherapy and radiotherapy. To elucidate the roles of the individual TTCCs in vivo we created RCAS/Tva-shTTCC mice for silencing of Cav3.1 and Cav3.2. The silencing of the TTCCs individually decreased tumor growth as measured by MRI and H&E staining. Silencing of TTCCs extended survival of mice in vivo. Silencing of TTCC decreases proliferation (Ki67) and increases apoptosis (Caspase 3). Our findings suggest T-type calcium channels contribute to tumor initiation and progression.