Credit: Ms Etsuko Uno, Walter and Eliza Hall Institute of Medical Research
An artist’s impression of the KAT6A and KAT6B genes, which are being inhibited by new molecules (red) that could help put cancer to sleep.

Australian scientists have taken a “major step forward” in the world of cancer research with the discovery of a new type of drug that can put cancer cells in animals into a permanent state of sleep.

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The drugs, which have been nearly a decade in the making, are the first of their kind: they stop cancer cells from reproducing without the harmful side effects caused by conventional cancer therapies.

“We are extremely excited about the potential that they hold as an entirely new weapon for fighting cancer,”

– Associate Professor Tim Thomas from Walter and Eliza Hall Institute of Medical Research, who co-led the study.

The research was published last week in the journal Nature, found the drugs were effective in halting the progression of blood and liver cancers in mice, as well as in delaying cancer relapse.

Credit: Ms Etsuko Uno, Walter and Eliza Hall Institute of Medical Research
Lead researchers Associate Professor Tim Thomas, Associate Professor Anne Voss and Professor Jonathan Baell.

More than two decades ago, a group of scientists began delving into embryonic development to better understand how our cells are directed to make us as we are. It started as curiosity-driven basic research, but has now led to the discovery of a wholly new class of anti-cancer drugs that can stop specific cancer cells from proliferating – putting them to “sleep,” potentially permanently.

“This new class of compounds stop cancer cells dividing and proliferating by switching off their ability to continue the cell cycle,”

“The technical term is cell senescence, but essentially the cells are put to sleep. The cancer cells aren’t dead, but they are effectively stopped in their tracks.”

– Joint research leader Associate Professor Anne Voss of the Walter and Eliza Hall Institute of Medical Research and the University of Melbourne.

Chemotherapy and radiotherapy work by causing irreversible DNA damage. Cancer cells are unable to repair this damage and die. The downside is that the therapies cannot be targeted only to cancer cells, and cause significant damage to healthy cells as well. This causes well-known short-term side effects, such as nausea, fatigue, hair loss and susceptibility to infection, as well as long-term effects such as infertility and increased risk of other cancers developing.

This new compound targets KAT6A and KAT6B, enzymes known to be involved in cell proliferation and to drive cancer when mutated. Dysregulation of the KAT6A/B functions caused by DNA rearrangements is frequently associated with blood and solid cancers. Studies have shown that the deletion of one KAT6A gene copy quadrupled the median survival of mice with lymphoma, suggesting that the suppression of KAT6A/B could have therapeutic benefits in cancer.

Through the screening of 243,000 small-molecule compounds and additional medicinal chemistry optimization, the researchers discovered a potent, selective inhibitor of KAT6A and KAT6B, named WM-8014. Treatment with WM-8014 promoted senescence (the gradual deterioration of function characteristic of most complex lifeforms) and suppressed the growth of lymphoma cells grown in the lab, and of cancer cells in a zebrafish model of liver cancer, without affecting the growth of healthy liver cells.

These molecules were thus able to induce senescence in cancer cells without causing DNA damage or affecting healthy cells, putting them to sleep indefinitely. While the study hasn’t yet looked into what happens to the “sleeping” cells afterward, the researchers believe that the immune system will eventually recognize them and clear them out. Future work will examine that, as the molecules are prepared for eventual human clinical trials.

“But with perseverance and commitment, we are excited to have developed a potent, precise and clean compound that appears to be safe and effective in our preclinical models. Our teams are now working on developing this compound into a drug that is appropriate for human trials.”

– Professor Jonathan Baell from the Monash Institute of Pharmaceutical Sciences