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Molecule stresses cancer to death
Swedish and French researchers have discovered a molecule that stresses aggressive cancer cells to death.
"I am convinced that we will be able to cure glioblastoma, as well as other aggressive cancer types," says Leif Eriksson, professor of chemistry at the University of Gothenburg.
Proteins are the primary "workforce" of a cell. They ensure that the right substances are produced in the correct amounts at the right time. A significant portion of a cell's proteins is made in the "protein factories": the ribosomes. From there, the proteins are transported to an organelle (the cell's equivalent of an organ) called the ER (Endoplasmic Reticulum), where they are folded into their correct three-dimensional shape.
An imbalance can occur when the amount of produced proteins exceeds the folding capacity of the ER. In such cases, unfolded or misfolded proteins "pile up" inside the ER. This imbalance is known as ER stress. If left unchecked, it can lead to cell death.
To protect against this, cells have a stress management system called the UPR (Unfolded Protein Response). During ER stress, this system is activated to manage the stress and restore balance.
How to Crash
Cancer Cells' Defenses
All cells are equipped with the stress management system UPR, which they can activate to survive short-term stress. However, in most healthy cells, this system is used very sparingly.
In aggressive cancer types—such as glioblastoma, triple-negative breast cancer, pancreatic cancer, and certain liver cancers—the UPR system must instead be constantly activated. These cells, as part of their aggressiveness, have a significantly increased protein production. As a result, the ER is under constant pressure to maintain a high rate of protein folding, and the stress management system UPR is utilized to keep the cells alive.
"This is where our research comes in. When we can stop the cancer cells' stress management system, the cancer cells become overloaded and die," explains Leif Eriksson.
With this in mind, Leif Eriksson and his team have worked for several years to explore the possibility of targeting the protein "IRE1," a key sensor for overloading in the ER, with a small inhibitor molecule. They have used advanced computer-based searches in large molecular databases. By studying the interaction between these molecules and the binding pocket of IRE1, they have successfully identified a compound: Z4. This compound has proven to be non-toxic to healthy cells at very high concentrations and can block IRE1.
Z4P is the key
However, Z4 does not pass the blood-brain barrier. Therefore, the team investigated possible variants of Z4 and ultimately found what they were looking for: the molecule Z4P. It can cross the blood-brain barrier, block IRE1, and thereby overload the stress management system UPR in cancer cells.
"Our long-term studies on mice with glioblastoma have shown that when the mice were given chemotherapy (Temozolomide) together with Z4P, they became completely free of their tumors, with neither side effects nor relapses," says Leif Eriksson, and continues:
"Treating mice is one thing. We want to cure humans. That’s why we have worked hard to systematically improve certain necessary properties of Z4P."
"The mice became completely free of their tumors, with neither side effects nor relapses."
High survival rates
Using a supercomputer, the researchers generated over 500,000 different variants of the compound. The top 100 were then synthesized and tested in protein analyses and cell lines. This resulted in the team identifying three molecules that were tested further. On their own, these molecules significantly reduce tumor growth. The best among them has a survival profile very similar to that seen in mice treated solely with the chemotherapy drug Temozolomide — but it is not toxic to healthy cells!
In combination treatments with the researchers' preferred compound and Temozolomide, the results have shown very high survival rates for the mice.
More funding is needed
Leif Eriksson and his colleagues are now moving forward with their work to further improve the results and determine the optimal dosage and treatment duration. Regulatory aspects must be considered, the best way to administer the compound as a drug needs to be investigated — and much more.
This involves extensive modeling, synthetic and medicinal chemistry, tests, analyses, preclinical studies, and administrative/regulatory work. And it costs. Testing on humans cannot begin until funding is secured.
"We are close. I am convinced that we will be able to cure glioblastoma, as well as other aggressive cancer types. But we need help to get all the way there," says Leif Eriksson.
