Abstract A73: Antisense oligonucleotides targeting ENO2 have selective anti-proliferative effects in glioblastoma cell with 1p36 genomic loss

Abstract

Abstract Essential cellular processes are often supported by redundant genes and pathways. Cancer cells frequently harbor deletions or mutations in essential genes and survive because of this functional redundancy. Identification of recurrent events that leave cancer cells selectively sensitive to inhibition of a particular pathway or gene can provides the opportunity to develop therapeutics with a high degree of selectivity for cancer cells over normal cells. In Glioblastoma Multiform (GBM), one of the most malignant brain cancers, roughly 3-5% of tumors have loss of the chromosome locus 1p36. Among the genes lost at this locus, is enolase1 (ENO1). Loss of ENO1 is tolerated by the cancer cells and is not required for cancer initiation or progression; likely because of functional redundancy with the closely related paralog, ENO2. However, it has been recently demonstrated that cancer cells with homozygous ENO1 loss are selectively sensitive to ENO2 inhibition. Here we investigate the potential of Antisense Oligonucleotides (ASO) targeted to ENO2 as a therapeutic approach to treat GBM with 1p36 loss of ENO1.We show that constrained ethyl (cET) modified ASOs targeting ENO2 produced dose dependent inhibition of ENO2 RNA and protein levels in GBM cells when delivered by free uptake. ASO-mediated ENO2 depletion led to the selective inhibition of ENO1-null cells and not the isogenic cells engineered to express ENO1. Moreover, cell cycle analysis is demonstrated that ENO2 depletion resulted in impaired proliferation due to unsuccessful transition of cells from G1 to S phase of the cell cycle. These findings support the application of ASO to elicit synthetic lethality in GBM tumors with 1p36 loss. Citation Format: Maria Shahmoradgoli, Curt Mazur, Youngsoo Kim, Brett P Monia, A. Robert Macleod, Florian M Muller, Christopher E Hart. Antisense oligonucleotides targeting ENO2 have selective anti-proliferative effects in glioblastoma cell with 1p36 genomic loss. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A73.