Researchers have created special molecules known as splice-switching oligonucleotides (SSOs) that target the RNA molecules responsible for encoding a protein called REST. In neuroendocrine tumors, these RNA molecules are spliced together incorrectly, contributing to the cancerous behavior of the cells. By injecting SSOs into tumors in mice, researchers have observed a restoration of normal REST function, leading to a reduction in tumor size. This innovative approach shows potential as a new tool for treating neuroendocrine tumors that do not respond to traditional therapies.
Neuroendocrine tumors, such as small cell lung cancer and neuroendocrine prostate cancer, are highly aggressive and prone to spreading. Unfortunately, many patients develop resistance to existing treatment options, resulting in poor outcomes. Researchers are now focusing on developing novel therapeutic strategies that target the specific molecular mechanisms of these tumors.
In a recent publication in Molecular Therapy: Nucleic Acids, a research team at Osaka University discusses a strategy that targets a key mechanism called RNA splicing.
RNA splicing is a crucial process in which cells remove certain segments of messenger RNA (mRNA) molecules to create mature mRNA that contains instructions for producing specific proteins encoded by genes. Errors in RNA splicing can lead to the production of dysfunctional or overly active proteins, significantly contributing to disease development.
The researchers focused on a protein called the RE1-silencing transcription factor (REST), which normally suppresses genes associated with neuroendocrine characteristics. Interestingly, an abnormally spliced form of REST mRNA is highly expressed in neuroendocrine tumors.
Lead author of the study, Keishiro Mishima, explains, “Incorrect splicing of REST mRNA can result in the loss of protein function, leading to the development of neuroendocrine cancer. Our goal was to develop a molecular approach to correct the splicing of REST.”
The team utilized molecules called amido-bridged nucleic acid-based splice-switching oligonucleotides (SSOs) designed to interact with specific regions of the REST mRNA molecule, enabling it to splice correctly. The researchers implanted neuroendocrine tumor cells under the skin of mice to form tumors. The mice were then injected with either saline or SSO, and tumor growth was monitored, along with blood sample collection.
“We evaluated specific biochemical markers in the mice’s blood samples to ensure that the SSO treatment did not cause liver toxicity,” stated senior author Masahito Shimojo. “Additionally, we treated neuroendocrine cancer cell lines with the SSOs in culture to support our findings from the animal studies.”
Treatment with REST SSOs resulted in a significant reduction in viable cancer cells compared to the control treatment. Furthermore, mice injected with REST SSOs exhibited a marked decrease in tumor size. The team then conducted further molecular analyses to assess the gene expression patterns controlled by REST under normal circumstances.
“After treatment, the levels of gene expression controlled by REST notably decreased in tumors treated with SSOs compared to those treated with the control,” explained Shimojo. “This suggests that the SSO helped restore REST function.”
Overall, the study illustrates that this innovative therapeutic approach shows promise for challenging neuroendocrine cancers.
