Cell death pathway points to a new way to target leukaemia

An international team of scientists has potentially unlocked an entirely new approach to targeting the blood cancer acute myeloid leukaemia, bringing hope to patients who are no longer responding to existing treatments. Their findings, published in the journal Nature Cancer, are significant not only for advancing the treatment of blood cancers — which are often diagnosed when they have already spread through the body — but potentially other types of cancer too.

The researchers made their discovery while investigating why a new class of drug, imetelstat, was effective at killing leukaemia cancer cells in the laboratory. As explained by lead author Dr Claudia Bruedigam, from the QIMR Berghofer Medical Research Institute, “We were interested in … imetelstat because it targets the telomeres, which are DNA sequences at the end of chromosomes.

“We used cutting-edge functional genetics experiments to basically knock out every single gene of the human genome in the patient samples to try to understand why it was effective against leukaemia.”

They found the drug induces a type of cell death that was discovered only a decade ago, known as ferroptosis. Scientists have only just begun to explore the potential of ferroptosis, which is distinctly different to other types of cell death such as apoptosis, and so could provide untapped methods of targeting cancers.

“It really was a ‘eureka moment’ when we found there was this other separate process taking place,” Bruedigam said. “That was incredibly exciting.”

The scientists also managed to show the detailed biological process that triggers ferroptosis in leukaemia samples treated with imetelstat. They found that the drug enters the leukaemia cancer cell and interacts with two important enzymes that regulate fatty acid metabolism. This causes changes that lead the cell membrane to rupture, which eventually results in leukaemia cell death.

By increasing our understanding of this new cell death pathway, the team’s research could be significant not only for treating for blood cancers, but other cancers as well. According to senior author Professor Steven Lane, also from QIMR Berghofer, “Having this extra weapon in our arsenal would create so much opportunity, particularly in combining this drug, and others like it, with existing treatments like chemotherapy and other novel cancer therapies.

“This could transform the way we think about treating patients with blood cancers, especially those who have run out of options.”

The findings have led to a phase II clinical trial of the drug in patients with myelodysplasia and acute myeloid leukaemia, which is underway at the Royal Brisbane and Women’s Hospital and Royal Adelaide Hospital in Australia as well as sites in Germany and France. Lane said the trial is currently at the halfway mark, with the team looking to recruit another 25 patients.

“The trial has only been open for a couple of months but we have already seen some really promising signs,” Lane said. He added that while the work is at an early stage of discovery, it could lead to a new therapeutic strategy for blood cancer patients.

“This is very exciting because it essentially means we potentially have a new weapon to kill blood cancer cells and an instruction manual that explains how the weapon works,” Lane said.

Image credit: iStock.com/Nemes Laszlo