A k-mer based transcriptomics approach for antisense drug discovery targeting the Ewing’s family of tumors
Year: 2018
Type: article
Abstract: // Andrew J. Annalora 1 , Shawn O’Neil 2 , Jeremy D. Bushman 3 , James E. Summerton 3 , Craig B. Marcus 1 and Patrick L. Iversen 1, 4 1 Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA 2 Center for Genome Research and Biocomputing, Oregon State University, Corvallis, OR 97331, USA 3 Onco-Tools, LLC, Philomath, OR 97370, USA 4 LS Pharma, LLC, Grand Junction, CO 81507, USA Correspondence to: Andrew J. Annalora, email: [email protected] Keywords: antisense oligonucleotides; phosphorodiamidate morpholino oligomers; transcriptomics; Ewing’s family of tumors; RNA-based therapeutics Received: May 10, 2018 Accepted: June 19, 2018 Published: July 17, 2018 ABSTRACT Ewing’s sarcoma treatment failures are associated with high mortality indicating a need for new therapeutic approaches. We used a k-mer counting approach to identify cancer-specific mRNA transcripts in 3 Ewing’s Family Tumor (EFT) cell lines not found in the normal human transcriptome. Phosphorodiamidate morpholino oligomers targeting six EFT-specific transcripts were evaluated for cytotoxicity in TC-32 and CHLA-10 EFT lines and in HEK293 renal epithelial control cells. Average morpholino efficacy (EC 50 ) was 0.66 ± 0.13 in TC-32, 0.25 ± 0.14 in CHLA-10 and 3.07 ± 5.02 μM in HEK293 control cells (ANOVA p < 0.01). Synergy was observed for a cocktail of 12 morpholinos at low dose (0.3 μM) in TC-32 cells, but not in CHLA-10 cells. Paired synergy was also observed in both EFT cell lines when the PHGDH pre-mRNA transcript was targeted in combination with XAGE1B or CYP4F22 transcripts. Antagonism was observed when CCND1 was targeted with XAGE1B or CYP4F22, or when IGFBP-2 was targeted with CCND1 or RBM11. This transcriptome profiling approach is highly effective for cancer drug discovery, as it identified new EWS-specific target genes (e.g. CYP4F22, RBM11 and IGBP-2), and predicted effective antisense agents (EC 50 < 1 μM) that demonstrate both synergy and antagonism in combination therapy.
Source: Oncotarget
Institutions: Oregon State University, Lo.Li. Pharma S.r.l. (Italy)
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W2884649451