Scientists at Rutgers Health and other institutions have made a major discovery about why a common leukemia drug stops working in many patients—and how to make it effective again.
This research could lead to better treatment for people with acute myeloid leukemia (AML), a serious type of blood cancer.
The drug venetoclax (sold as Venclexta) is used to treat AML. It works by helping cancer cells die. While it often helps at first, most patients eventually stop responding to the drug.
This means the drug no longer works, and the cancer comes back. The survival rate for AML is still low, with only about 30% of patients living five years after diagnosis.
The scientists wanted to understand why venetoclax becomes less effective. They discovered that leukemia cells can change the shape of their mitochondria.
Mitochondria are the parts of the cell that produce energy, and they also play a role in cell death. When mitochondria change shape, they can protect cancer cells from the drug. This helps the cancer cells survive longer.
The researchers identified a protein called OPA1 that helps mitochondria change their shape. Cancer cells that become resistant to venetoclax produce too much OPA1.
This protein changes the inside of the mitochondria in a way that traps a molecule called cytochrome c. Normally, cytochrome c is released to help the cell die, but when it is trapped, the cell avoids death.
Using advanced tools like electron microscopes and genetic tests, the researchers confirmed their findings. They also looked at real samples from leukemia patients and saw that patients who had relapsed after treatment had more OPA1 and changes in their mitochondria compared to newly diagnosed patients.
To see if they could reverse this resistance, the scientists tested two new drugs that block OPA1. These OPA1 inhibitors were developed by researchers in Italy.
When these new drugs were combined with venetoclax and tested in mice that had human leukemia, the results were very promising. The mice lived twice as long as those that only received venetoclax.
This combination therapy worked even in tough cases, like leukemia with p53 mutations. These mutations are known to make the disease harder to treat and more resistant to drugs.
The study also found that when OPA1 is blocked, cancer cells become more dependent on a nutrient called glutamine and are vulnerable to a type of cell death called ferroptosis, which involves damage caused by iron. The good news is that the OPA1-blocking drugs did not harm the development of normal blood cells in the mice.
Even though these results are encouraging, the research is still in its early stages. The new drugs need more testing and improvements before they can be used in humans. Researchers are working on making these drugs more suitable for people by improving how they dissolve in the body and how well they work.
Still, this discovery offers new hope. Blocking OPA1 could help make venetoclax work again for many leukemia patients. It might also help treat other types of cancer, like breast and lung cancer, where OPA1 is also linked to drug resistance and poor outcomes.
This breakthrough gives scientists a new way to fight cancer by targeting the shape and function of mitochondria. It also shows the importance of understanding how cancer cells avoid death and how we might stop them.
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The study is published in Science Advances.
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