A gapmer antisense oligonucleotide targeting SRRM4 is a novel therapeutic medicine for lung cancer

Abstract

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.

Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

“…Remarkably, we found that SRRM4 was the only SF significantly upregulated in NFPTs, which was also associated with higher chiasmatic compression. These results compare nicely with the overexpression of SRRM4 reported in small cell lung cancers and in neuroendocrine prostate cancers, where SRRM4 was also correlated with poor patient survival [56,57].…”

Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer

“… 18 Therefore, nucleic acid drugs potentially serve as a better approach to targeted therapy than therapeutic antibodies. The strengths of our AmNA-ASOs are as follows: (1) oligonucleotide sequences with enhanced target specificity, lack of significant homology with the mouse counterpart of SYT13 , and minimal toxicity; (2) chemical modifications extend the half-life of therapeutic ASOs to prolong exposure of tumors on the peritoneal wall; 8 , 32 (3) higher binding affinity to target molecules that enhance drug efficacy; 33 and (4) chemical modifications that change the lipophilicity of ASOs to confer resistance to absorption in the peritoneal cavity. 7 , 34 The two ASOs studied here were carefully selected from 71 sequences through multistep screening for high knockdown efficacy, effective in vitro activity, and potentially minimal off-target effects.…”

“…ASOs used to treat various disorders are in different phases of clinical trials, and some nucleic acid drugs are approved for treating retinitis, homozygous familial hypercholesterolemia, and Duchenne muscular dystrophy. 8 , 11 , 32 However, over the past two decades, ASO-based cancer therapy has been unsuccessful despite substantial efforts directed toward developing rational oligonucleotide strategies to silence gene expression. 7 , 32 Vulnerability to endogenous nucleases, poor delivery to solid cancer tissues, and insufficient disease specificity of the target molecules represent serious obstacles to the clinical use of ASOs.…”

MicroRNA-4516-mediated regulation of MAPK10 relies on 3′ UTR cis-acting variants and contributes to the altered risk of Hirschsprung disease

“…MiR-4516, located in the cytoplasm,23 has important regulatory functions in multiple pathological conditions, such as HIV-associated neurocognitive disorder, thyroid carcinomas and lung cancer 24–26. Meanwhile, some targets and signalling pathways may underlie miR-4516-mediated functions.…”