Novel Approach to Target Cancer Cells
17 January 2025
Scientists of the Institute of Biological Information Processing (IBI-2, Mechanobiology) have developed a novel approach for cancer treatment that utilizes a special RNA molecule to selectively target and destroy glioblastoma cancer cells. This approach, termed selectively expressed RNA (seRNA), involves the expression of a specific RNA molecule that directs the production of a protein within the targeted cancer cells, leading to their own programmed cell death. In healthy cells, the seRNA remains inactive and exhibits no detrimental effects. This innovative strategy has been confirmed also in mouse studies, and the findings have been recently published in the renowned journal Nature Communications. The method is based on a newly developed and easily adaptable platform technology, which has the potential to form the basis for developing a new generation of effective drugs not only against cancer, but also against viral or genetic diseases such as cystic fibrosis.
In cancer research, the long-term goal has been to develop drugs that only attack tumor cells and do not cause side effects in healthy cells. The active drug must therefore be able to distinguish between healthy and diseased cells. Jülich scientists have developed an RNA molecule that is only active in diseased cells, where it leads to the production of the active compound. The new RNA form was characterized in detail in close cooperation with scientific partners from Cologne, Würzburg, and Strasbourg.
Since the development of the vaccine against SARS-CoV-2, messenger RNA (mRNA) is no longer an unknown. Within cells, it is responsible for decoding the genetic blueprint of DNA and utilizing this information to initiate the production of various molecules, predominantly proteins, which are essential for cell metabolism.
Messenger ribonucleic acid (mRNA) molecules are known to be constantly active in all cells. This property stands in contrast to that of seRNA molecules. Their activation is initiated by the combination of the green-labeled building block of the seRNA (antisense) with a specific RNA (target sense RNA) that is exclusively present in the selected target cell, thereby forming a double strand. This double strand serves as an alarm signal for the cell, causing the seRNA to be partially degraded. This degradation subsequently activates the remaining seRNA. This process ultimately leads to the production of an enzyme that initiates the programmed cell death of cancer cells (illustrated in the figure by the orange building block, designated as the "effector"). The specific enzyme produced can be selected based on the intended application. In healthy cells, the seRNA remains inactive due to the absence of cancer-specific RNA. This mechanism circumvents the potential for adverse effects, and the inactive seRNA is rapidly broken down by natural processes within a few hours without leaving any residue.
Jülich researchers have now expanded upon this principle by developing a selectively expressed RNA (seRNA) composed of multiple building blocks. One important component is a sensor that is highly specific and capable of discerning between healthy and diseased cells. In a diseased cell, such as a glioblastoma cell, this sensor binds to a tumor-specific mRNA, such as a cancer marker, to form an RNA double strand. The cell interprets this as a potential viral attack, leading to the partial degradation of the seRNA. This, in turn, activates the subsequent components of the seRNA complex, leading to the production of an enzyme that causes the cancer cell to self-destruct. The choice of seRNA building blocks determines the specific target cell and the resulting medical active protein (enzyme). In healthy cells, this process does not occur due to the absence of the cancer marker, ensuring that healthy cells are not targeted.
"The utilization of the cell's own RNA as a 'switch' constitutes a wholly novel approach," explains PD Dr. Bernd Hoffmann from the IBI-2. He further elaborates on the modular principle, stating that it renders seRNA a promising platform technology. The method's versatility is evident in its potential applications, including the treatment of various cancers, hepatitis B, and autoimmune diseases. As Prof. Rudolf Merkel, director of IBI-2, explains, "With the development of seRNA molecules for medical applications, we can ensure the targeted attack of diseased cells and at the same time combine this with the selective production of active agents.
IBI-2 is committed to the advancement of switchable seRNA molecules as part of a contractual research agreement, with the objective of optimizing their application against glioblastoma and other diseases. The novel platform technology will soon undergo the preclinical phase and preliminary toxicological studies for liver cancer. SRTD biotech holds the intellectual property rights for the seRNA technology.
Video: A new chapter in treating disease.
Original publication:
Selectively expressed RNA molecules as a versatile tool for functionalized cell targeting, Nature Communications, by Frederik Rastfeld, Marco Hoffmann, Sylvie Krüger, Patrick Bohn, Anne-Sophie Gribling-Burrer, Laura Wagner, Nils Hersch, Carina Stegmayr, Lukas Lövenich, Sven Gerlach, Daniel Köninger, Christina Hoffmann, Helene L. Walter, Dirk Wiedermann, Hajaani Manoharan, Gereon R. Fink, Rudolf Merkel, Heribert Bohlen, Maria A. Rueger, Bernd Hoffmann, DOI: 10.1038/s41467-024-55547-6