Neuroendocrine tumors, including small cell lung cancer and neuroendocrine prostate cancer, are particularly aggressive and often resistant to current treatments, resulting in poor patient outcomes. In response, researchers are exploring new therapeutic methods targeting the specific molecular mechanisms of these tumors.
RNA Splicing and Its Role in Neuroendocrine Tumors
In a recent article published in Molecular Therapy: Nucleic Acids, researchers at Osaka University detail a strategy targeting RNA splicing, a critical cellular process. RNA splicing involves the removal of specific portions of messenger RNA (mRNA) molecules, producing mature mRNA that directs protein synthesis. Errors in RNA splicing can lead to dysfunctional or overactive proteins, contributing significantly to disease development.
The focus of the study was the RE1-silencing transcription factor (REST), a protein that represses genes supporting neuroendocrine phenotypes. Abnormally spliced REST mRNA is found at high levels in neuroendocrine tumors. “Incorrect splicing of REST mRNA can cause the resulting protein to lose its function, which can lead to neuroendocrine cancer development,” explains Keishiro Mishima, lead author of the study. “Our group aimed to develop a molecular method that could be used to correct REST splicing patterns.”
Innovative Use of Splice-Switching Oligonucleotides
The team developed a molecular method to correct REST splicing patterns using amido-bridged nucleic acid-based splice-switching oligonucleotides (SSOs). These SSOs are designed to interact with a specific portion of REST mRNA, promoting proper splicing into its normal form.
To test this approach, the researchers implanted neuroendocrine cancer cells under the skin of lab mice, forming tumors. The mice were then injected with either saline or SSO and monitored for tumor growth and blood sample biochemical markers. “We examined the levels of certain biochemical markers in the mice serum samples to ensure the SSO treatment did not induce any liver toxicity,” explains Masahito Shimojo, senior author of the study. “In parallel, we treated neuroendocrine cancer cell lines in culture with the SSOs to obtain in vitro data to support our in vivo findings.”
Promising Results from REST SSO Treatment
The REST SSO treatment significantly reduced the number of viable cancer cells and tumor size in the mice compared to the control treatment. Molecular analyses revealed that gene expression levels typically repressed by REST were significantly lower in SSO-treated tumors, indicating restored REST function. “Following treatment, REST-controlled gene expression levels significantly decreased in SSO-treated tumors compared with the control-treated tumors,” Shimojo notes. “This indicated that the SSO promoted the restoration of REST function.”
This study demonstrates that targeting RNA splicing with SSOs is a promising therapeutic approach for treating intractable neuroendocrine cancers. The innovative technique offers hope for improved patient outcomes in these aggressive tumor types.
Publication Details
Splice-switching antisense oligonucleotide controlling tumor suppressor REST is a novel therapeutic medicine for neuroendocrine cancer. Mishima, Keishiro et al. Molecular Therapy - Nucleic Acids, Volume 0, Issue 0, 102250. https://doi.org/10.1016/j.omtn.2024.102250