One way to kill cancer cells may be to hit them while they’re down — stress out the cells while blocking their ability to recover from that stress.
In a new study published in Science Translational Medicine, scientists introduce a gene important for acute myeloid leukemia (AML) cells to repair their DNA, and a new small molecule inhibitor that blocks it, resulting in cancer cell death. The new molecule allowed mice to survive longer when the scientists used it by itself or in combination with drugs that cause DNA damage. Already in Phase 1 clinical trials, this new molecule may soon be able to treat patients with some of the most aggressive forms of leukemia.
“We know that cancer cells are very sensitive to stress response and have different ways to respond to cellular stress compared to normal cells,” said Lina Benajiba, a physician scientist at the University of Paris in France and co-senior author of the study. “We thought that we might find a therapeutic window where we could have a target to preferentially target leukemic cells.”
By screening more than 400 cell-stress-related genes in a mouse model of AML, the researchers found that when mice lost expression of valosin-containing protein (VCP), they survived longer. When the scientists treated cancer cells taken from AML patients with a VCP inhibitor, fewer cancer cells grew.
Cells express VCP in both the nucleus and the cytoplasm, but the researchers found that if they forced VCP out of the nucleus, AML cells died, suggesting that VCP is needed in the nucleus of AML cells, possibly to help repair DNA.
“When we impair at a very low dose, VCP, what happens is that there is an impairment of the nuclear fraction of VCP, and that actually kills the cells,” Benajiba explained. “Normal cells would need a higher block of VCP before dying.”
As they worked out how VCP inhibition kills cancer cells, Benajiba’s team initiated a collaboration with the biotech company, Cleave Therapeutics. The company previously developed a VCP inhibitor, but clinical trials with the molecule halted when patients developed impaired vision. But, working together, the team developed a new small molecule VCP inhibitor called CB-5339 that is similar in structure to the first-generation inhibitor, but did not have the same off-target effects on cells in vitro.
When they tested their new VCP inhibitor in mice, the researchers found that the mice survived longer. Most promisingly, when they treated mice with their new molecule in combination with chemotherapy, mice survived even longer than with either treatment alone.
“It’s a really elegantly performed study,” said Marc Mansour, a clinical scientist at University College London, who was not involved in the research.
“They saw, certainly deep and really good evidence of synergy by activating DNA damage and inhibiting VCP,” he added. “Dosing these things in mice and dosing them in humans is a totally different kettle of fish, and actually seeing what is sustainable in terms of toxicity in humans is going to be the key thing.”
The researchers are currently testing the new VCP inhibitor in patients in Phase 1 clinical trials with the first results expected within the next year.
“For diseases such as AML, where the survival of patients is still very poor, I think it’s important that we can quickly translate what we find in the lab because the patients really, really need the new discoveries,” Benajiba said. “I’m really happy that this work was really translated so quickly to patients.”