Combining inhibitors to treat AML


Lab mouse

Preclinical research has revealed a treatment approach that could prove effective against acute myeloid leukemia (AML).

Researchers tested the IAP inhibitor birinapant in combination with p38 inhibitors and observed antileukemic activity in mouse models of AML and samples from patients with the disease.

Combination treatment proved more effective than either agent alone, and the combination was less toxic than single-agent chemotherapy.

Najoua Lalaoui, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and her colleagues conducted this research and relayed the results in an article published in Cancer Cell.

The researchers generated several mouse models of AML—MLL-ENL ± NRasG12D, MLL-AF9 ± NrasG12D, AML1-ETO9a + NrasG12D, CBFβ-MYH11 + NrasG12D, NUP98-HoxA9, and HoxA9/Meis1.

In these models, the team tested birinapant with 1 of 2 p38 inhibitors—LY2228820 or SCIO-469—or with the MK2 inhibitor PF-3644022. They said each combination “dramatically” increased cell death, when compared to birinapant alone, in most models. The exceptions were AML1-ETO9a + NrasG12D and CBFβ-MYH11 + NrasG12D.

Next, the researchers tested LY2228820 plus birinapant in samples from 8 AML patients. The samples had FLT3-ITD mutations (patients 1, 2, 4, 6, and 7), a FLT3 D835 missense mutation (patient 4), nucleophosmin exon-12 mutations (patients 2 and 4), an MLL translocation (patient 3), inv(3) (patient 1), and inv(16) (patient 8).

All 8 samples were sensitive to birinapant alone. And although LY2228820 alone did not induce cell death in any of the samples, the drug had a synergistic effect with birinapant in 4 of the samples (patients 2, 3, 4, and 7).

The researchers also found that peripheral blood mononuclear cells from healthy donors proved more resistant to combination LY2228820 (at 10 µM) and birinapant (at 500 nM) than to cytarabine (10 µM), daunorubicin (at 0.4 µM), or idarubicin (at 0.4 µM).

In addition, 4 weeks of treatment with birinapant and LY2228820 was well-tolerated in mice without tumors.

Finally, the researchers tested birinapant and LY2228820, either alone or in combination, in mouse models of MLL-ENL, MLL-AF9, and NRasG12D mutant/MLL-AF9/Luc AML.

Combination treatment prolonged survival in all 3 models, when compared with mice that received single agents or no treatment. However, unlike in the MLL-ENL and MLL-AF9 models, the combination was unable to cure NRasG12D mutant/MLL-AF9/Luc mice of their leukemia.

“Our findings have made us hopeful that a combination of birinapant and a p38 inhibitor may be more effective in treating AML than current therapies and also have less toxicity for patients,” Dr Lalaoui said.

“We tested forms of AML that are highly resistant to chemotherapy and found that birinapant and p38 inhibitors could even kill these cancer cells, which is great news.”

Birinapant is being developed by TetraLogic Pharmaceuticals Corporation, and some of the researchers involved in this work reported relationships with the company.

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