Members of the Bio Network Analysis Laboratory led by Professor Yoosik Kim and PhD candidate Yongsuk Ku of the Department of Chemical and Biomolecular Engineering have recently identified the genetic reasons behind the historically questionable effectiveness of the drug decitabine. Also known by its brand name Dacogen, the drug inhibits cancer cell reproduction by altering DNA to activate certain genes. This drug is typically used to treat patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), which are both cancers involving an excess of immature blood cells in bone marrow, making it difficult for the bone marrow to develop healthy cells. The results of this research were published on March 30 in PNAS (Proceedings for the National Academy of Science of USA) under the title “Noncanonical immune response to the inhibition of DNA methylation by Staufen1 via stabilization of endogenous retrovirus RNAs”.

In the field of internal medicine, the best type of treatments are the ones that work alongside and improve the human body’s natural response. To this end, Dacogen is intended to trigger an elevated immune response to cancer cells. It alters DNA transcription to produce endogenous retroviruses (ERVs). These are dormant remnants of viruses that were inserted into the genetic sequence of our evolutionary ancestors. Rather than producing the entire virus, the drug causes our cells to produce double-stranded RNA (dsRNA) that matches the virus. These dsRNAs are considered foreign materials by the body and trigger an immune response. However, Dacogen only shows improvements in 30-35% of patients. In the majority of patients, the dsRNA degrades before any physiological response can occur from the immune system. The researchers investigated the molecular mechanisms behind the production and transport of these dsRNAs within the cell to find out why there was such a significant disparity in effectiveness of Dacogen.

The researchers used RNA interference (RNAi) screening, which deactivates specific sequences along the genome and affects protein synthesis within the cell. It was found that when genome sequences that produced the proteins Staufen1 and TINCR were inhibited, the dsRNA produced by the drug degraded before it was able to stabilize. Through further research, the team discovered that Staufen1 and TINCR stabilized the dsRNA through either direct binding with the dsRNA or through forming a TINCR and a single strand ERV duplex. This allowed for ERV stabilization, which can be followed by a Type 1 immune response and protein synthesis. 

This research confirmed that Dacogen would show little effectiveness on patients with low levels of Staufen1 and TINCR, meaning MDS and AML patients who were confirmed to have low levels of these two proteins can now be provided alternative chemotherapy options. Professor Kim stated, “This serves as an important step towards developing patient-specific cancer treatment strategies”. The team intends to continue this research on cancers that have spread to blood through metastasis, and look to extend the application of this knowledge to solid tumor cancers.