Abstract B002: A therapeutically targetable positive feedback loop between long noncoding RNA-HLX-2-7, HLX, and MYC that promotes childhood cancer group 3 medulloblastoma

Abstract

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is categorized into four main molecular subgroups: wingless pathway (WNT)-activated, sonic hedgehog pathway (SHH)-activated, group 3 (G3), and group 4 (G4). Although the driver pathways for G3 and G4 MB are unclear, most of these tumors are characterized by c-Myc and MYCN signatures, respectively. Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma formation and progression. We have identified lncRNA, lnc-HLX-2-7, as an oncogene and a potential therapeutic target in group 3 (G3) medulloblastomas. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of its host coding gene HLX, a sense overlapping gene of lnc-HLX-2-7, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium oxide nanoparticle–coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-ASO-lnc-HLX-2-7) and lipid nanoparticle-coated HLX (LNP-si-HLX) inhibits tumor growth by 40-50% in an intracranial medulloblastoma xenograft mouse model (p<0.01). Combining nanoparticle-coated lnc-HLX-2-7 and HLX with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with monotherapy (p<0.01). Thus, the lnc-HLX-2-7–HLX–MYC axis is important for regulating G3 medulloblastoma progression, providing a strong rationale for using lnc-HLX-2-7 and HLX as therapeutic targets for G3 MBs. Citation Format: Ranjan R Perera. A therapeutically targetable positive feedback loop between long noncoding RNA-HLX-2-7, HLX, and MYC that promotes childhood cancer group 3 medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B002.