The survival of children with acute lymphoblastic leukemia (ALL) took a big leap in the 1970s when asparaginase became a regular part of treatment. But in some 15 percent of children with ALL, the disease comes back after treatment. Aside from developing new drugs, improving existing therapies such as asparaginase is therefore urgently needed.
Sensitivity
Scientists at the Princess Máxima Center looked for ways to increase the sensitivity of leukemia cells to asparaginase. In a new study, published this week in the prestigious journal Blood, the team systematically switched off particular genes in leukemia cells. In the lab they looked at which cells died faster after treatment with asparaginase. This gave them insight into how the cancer cells became more sensitive to the drug.
The researchers found 31 genes for which switching them off enhanced the effect of asparaginase in the ALL cells, including the BTK gene. The protein made by this gene is blocked by an existing drug, ibrutinib. The team chose this drug to study in more detail.
Few long term side effects
To find out whether ibrutinib improves the effect of asparaginase, the researchers compared the effect of the combination therapy with asparaginase alone. Tests on cultured leukemia cells, cells from patients, and in mice indeed showed that the combination therapy worked better.
Dr. Laurens van der Meer, co-leader of the study from the Van Leeuwen group: ‘With this addition, we can more effectively tackle the leukemia cells with asparaginase, a treatment that comes with relatively few long term side effects as it does not cause DNA damage, unlike many other drugs.’
Survival mode
Asparaginase breaks down the amino acid asparagine in the blood, which the leukemia cells need to grow. ‘Leukemia cells are unable make this amino acid themselves, unlike most healthy cells in our body. The lack of asparagine makes them go into a kind of survival mode,’ says dr. Frank van Leeuwen, head of the research group. ‘We now know that the addition of ibrutinib enhances the effect of asparaginase because it interferes with the metabolism of the leukemia cell. As a result, the survival mode is no longer enough and the cells die.’
The BTK gene plays a role in the normal development of white blood cells. As a result, ibrutinib works specifically on these cells, and the risk of side effects is relatively small. The drug is already being used in adults with other forms of blood cancer.
Clinical trial
Van Leeuwen: ‘The next step is to see whether combination therapy of asparaginase with ibrutinib also works better in patients. We hope to start a clinical study in children with very hard to treat forms of ALL, or in children whose disease comes back after treatment with CAR-T cell therapy.’
Butler M, et al., (2021) BTK inhibition sensitizes Acute Lymphoblastic Leukemia to asparaginase by suppressing the Amino Acid Response pathway. Blood. DOI: 10.1182/blood.2021011787
This study was partly funded by the Dutch Cancer Society, a personal grant from Radboudumc and a Scientific Exchange Grant from the European Organization for Molecular Biology (EMBO).