Abstract 5822: Targeting an immortalization mutation to control glioblastoma

Abstract

Abstract Glioblastoma multiforme (GBM), the most aggressive primary brain cancer, is a heterogeneous disease. Standard treatment of temozolomide and radiation therapy has remained unchanged for the past thirty years. However, over 80% of GBM tumors have a telomerase reverse transcriptase (TERT) promoter mutation, or TPM. Telomerase is an enzyme containing the catalytic subunit, telomerase reverse transcriptase (TERT), that mediates telomere elongation in the nucleus. In the absence of any effective molecular targeting therapy for GBM, the elucidation of oncogenic signaling of TERT could open new avenues in GBM treatment. Canonically, mutations of TERT, which result in TERT upregulation, maintain telomere length in the nucleus and promote indefinite proliferation of cancer cells. However, a non-canonical function of TERT in the mitochondria has recently been suggested. We screened GBM cell models against a novel small molecule inhibitor (RG1534, Reglagene Inc.) that interferes with the functionality of a mutated TERT promoter. RG1534 selectively suppresses glioma cell viability without affecting non-transformed normal human astrocytes. A dose dependent response was observed in glioma cell lines, resulting in a decrease in TERT mRNA expression. To validate this, TERT protein levels in glioma cells treated with RG1534 were measured and results showed a reduction in expression post treatment. More interestingly, RG1534 treatment leads to rapid induction of apoptosis in glioma cell line which does not correlate with the time course of the telomere shortening effect. Based on prior findings that mitochondrial TERT is involved in DNA damage, we conducted the fractionation of various glioma cell lines to measure the protein expression of TERT in subcellular compartments. We observed a higher expression of TERT in the mitochondria compared to the nucleus. This suggests that TERT may have non-canonical functions outside of telomeric elongation. In summary, our results demonstrate that non-canonical functions of TERT may play a critical role in glioma pathobiology and warrants further study. Citation Format: Jayashree S. Iyer, Nanyun Tang, Shayesteh R. Ferdosi, Vijay Gokhale, Laurence H. Hurley, Harshil D. Dhruv, Michael E. Berens. Targeting an immortalization mutation to control glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5822.