Cancer Gene Switches
Russian scientists are the first in the world to improve the technology of antisense oligonucleotides for cancer therapy
ITMO University scientists were the first in the world to propose the use of antisense oligonucleotides — synthesized short fragments of DNA — to destroy a cancer cell.
Researchers have developed a system that allows to simultaneously detect cancer markers in cells and "turn off" the genes responsible for tumor survival. The device can be changed for any cancer marker and target gene — this opens up opportunities for effective control of oncopathology.
Radiation therapy and chemotherapy are actively used for the treatment of oncological diseases. However, side effects and chemoresistance are forcing scientists to look for new ways to fight cancer. An alternative to these methods can be the technology of gene therapy, namely antisense oligonucleotides — single-stranded artificially synthesized short fragments of DNA. At the same time, there is a difficulty with the use of antisense agents as antitumor drugs: they can suppress the necessary genes in healthy cells as well.
ITMO University researchers have found a way to solve this problem: they have improved the usual technology of antisense agents so that instead of one target molecule, it recognizes two. To do this, they created a design based on binary antisense oligonucleotides to search for cancer markers and selective cleavage of malignant tumors. The system consists of two modules: sensory, which searches for special nucleic acids that signal the presence of cancer, and therapeutic, "catching" the target molecule that needs to be destroyed. Before ITMO scientists, no one had considered the technology of antisense agents for the cancer marker-dependent launch of cancer therapy.
"This technology allows you to kill cancer cells and leave healthy tissues intact. Our design forms a complex with the target RNA molecule of the gene of interest and the cancer marker. Then it interacts with the intracellular enzyme RNase H, which is able to cleave the RNA molecule. We tested the development in the presence and absence of an oncomarker. The system works 6 times more efficiently when it is available, which means that the cancer marker activates a device for selective destruction of the gene we need. In fact, we want to force the resources of the cell itself to destroy malignant formations," says Valeria Drozd, author of the study, engineer of the chemical and biological cluster of ITMO University.
The researchers tested the effectiveness of their proposed solution in vitro on an RNA fragment of the GFP (green fluorescent protein) gene. It is widely used as a luminous label in cellular and molecular biology to study the expression of cellular proteins. Scientists chose a fragment of the KRAS gene as an oncomarker. It is present in many types of cancer. About 27% of cases of oncological diseases in humans are associated with a mutation of the RAS family genes.
"We destroy the RNA of the GFP gene, which leads to a decrease in the number of fluorescent proteins (the cell begins to glow less). This test is necessary in order not to immediately destroy cells by affecting vital genes. It is important to make sure that the system purposefully turns off the desired gene in the presence of a cancer marker, and not because it is toxic in itself," explains Valeria Drozd. — We also tested the development for the recognition of mutations in the cancer marker. For example, if mRNAs of genes (informational RNAs) are taken as such markers, then they can be expressed in both healthy and cancerous tissues. In the latter, they will have a special mutation: one letter in the chain will be replaced by some other. We also need to recognize this letter so that the device responds specifically to tumor cells. Our system is able to detect nucleotide substitution in the cancer marker"
The design proposed by scientists can be modified for any system, any cancer marker and target gene — this opens up opportunities for future research.
Serious work is ahead for researchers to develop a strategy for chemical modification of antisense agents. It is important that the protective mechanisms inside living systems do not destroy the structure before it acts on a cancerous tumor. In addition, scientists are trying to identify the most vulnerable survival gene in cancer cells and a universal cancer marker suitable for several types of tumors at the same time.
Article by Drozd et al. Binary Antisense Oligonucleotide Agent for Cancer Marker-Dependent Degradation of Targeted RNA is published in the journal Nuclear Acid Therapeutics.
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