One-two punch treatment knocks out acute myeloid leukaemia

Wednesday, 08 May, 2024

One-two punch treatment knocks out acute myeloid leukaemia

A novel combination of two cancer drugs has shown great potential as a future treatment for patients with acute myeloid leukaemia (AML), one of the most common types of blood cancer. The discovery, published in the journal Cancer Cell, could soon lead to clinical trials, providing hope for the 1100 Australians diagnosed with AML annually.

Researchers at the Walter and Eliza Hall Institute (WEHI) paired venetoclax, a current standard-of-care anticancer drug for AML, with a STING agonist, an emerging class of immunotherapy drug. This marks the first time that a STING agonist has been used to directly target mechanisms within the cancer cells themselves, stimulating the natural processes that cause these cells to die.

Until now, STING agonist immunotherapy drugs have been chiefly used to attack solid tumours by activating the body’s immune response. But the new research indicates that they could be deployed against blood cancers, by directly targeting the cancer cells intrinsically.

The WEHI team examined samples from a range of different blood cancers, including AML, and treated them in the lab with the drug combination. As explained by co-senior author Associate Professor Gemma Kelly, a laboratory head in WEHI’s Blood Cells and Blood Cancer division, both venetoclax and the STING agonists played complementary roles in killing the cancer at the cellular level.

“Within a cancer cell, venetoclax blocks the machinery of the cell that is keeping it alive,” Kelly said. “In certain blood cancers where this response is suboptimal, STING agonists can supercharge this effect to deliver cancer a deathly blow.

“This is the one-two punch combo that could be the knockout blow for AML,” added co-first author Dr Sarah Diepstraten. “You could almost paraphrase the famous boxer Muhammed Ali and say this treatment floats like a butterfly and STINGs like a bee.”

Critically, the combination treatment showed promise in AML that was driven by a mutated p53 protein, which is generally more aggressive and harder to treat. The p53 protein is supposed to prevent the formation of cancerous cells by enforcing the death, or arresting the growth, of cells that have become damaged or abnormal — but when the protein is mutated and becomes defective in groups of cells, it can significantly boost a person’s risk of developing cancer.

“For AML patients that do not have as much therapy-induced death of their leukaemia cells due to this mutated protein, combining venetoclax with a STING agonist causes more killing of AML cells than treating with venetoclax alone,” Diepstraten said.

“The treatment was highly effective at killing cancer cells in samples with and without the p53 mutation, which is exciting given the lack of effective treatments for aggressive cancers driven by mutations in p53.”

WEHI lab head Professor Andrew Wei, co-senior author on the study, said that while further research is needed, the findings are highly promising.

“While early clinical trials in solid cancers have suggested STING agonists are well tolerated in the body, these results offer exciting new hope for patients with the most resistant forms of leukaemia,” Wei said.

“Given STING agonists are currently in clinical trials, we hope to conduct human studies using STING agonists in combination with venetoclax in the near future.

“The research findings … will inspire a completely new clinical approach for patients affected by the most resistant and deadly forms of acute leukaemia.”

WEHI is now translating these findings into a new clinical trial in AML patients in collaboration with Aculeus Therapeutics, a local biotechnology company which has spent the last several years developing a potent STING agonist. The proprietary drug, dubbed ACU-0943, is expected to enter clinical development for the treatment of AML later this year.

Image credit: Laszlo

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