A gapmer antisense oligonucleotide targeting SRRM4 is a novel therapeutic medicine for lung cancer.
Masahito ShimojoYuuya KasaharaMasaki InoueShin-Ichi TsunodaYoshie ShudoTakayasu KurataSatoshi ObikaPublished in: Scientific reports (2019)
Small cell lung cancer (SCLC) is the most aggressive neuroendocrine phenotype of the deadliest human lung cancers. However the therapeutic landscape for SCLC has not changed in over 30 years. Effective treatment and prognosis are needed to combat this aggressive cancer. Herein we report that Ser/Arg repetitive matrix 4 (SRRM4), a splicing activator, is abnormally expressed at high levels in SCLC and thus is a potential therapeutic target. We screened an effective gapmer antisense oligonucleotide (gASO) targeting SRRM4 in vitro which led to cell death of SCLC. Our gASO, which is stabilized by containing artificial nucleotides, effectively represses SRRM4 mRNA. We found that our gASO repressed SRRM4 synthesis leading to a dramatic tumor reduction in a lung cancer mouse model. We also analyzed miRNA microarray and found that the miR-4516 is abnormally increased in exosomes in the blood of SCLC patients. Treating with gASO suppressed tumors in the SCLC model mouse concurrently reduced plasma miR-4516. In conclusion this study reports that administration of an SRRM4-targeted gASO coupled with a novel miRNA diagnostic methodology represents a potential breakthrough in the therapeutic treatment of high mortality SCLC.
Keyphrases
- small cell lung cancer
- cell death
- cell proliferation
- mouse model
- end stage renal disease
- long non coding rna
- cancer therapy
- chronic kidney disease
- stem cells
- newly diagnosed
- mesenchymal stem cells
- ejection fraction
- emergency department
- peritoneal dialysis
- single cell
- human health
- risk factors
- young adults
- risk assessment
- bone marrow
- squamous cell
- binding protein
- nucleic acid
- smoking cessation