Diabetes Drugs Could Help Eradicate CML Stem Cells

Anti-diabetic drugs could help eradicate leukemic stem cells in chronic myeloid leukemia (CML) patients, according to a new study. This could mean that combination therapy with tyrosine kinase inhibitors could offer clinically relevant cancer eradication in CML patients.

“Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR–ABL have improved patient survival markedly,” wrote study authors led by Philippe Leboulch, MD, of the Institute of Emerging Diseases and Innovative Therapies in Paris. “However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells.” TKIs cannot eradicate the quiescent CML leukemia stem cells (LSCs).

In the new study, researchers combined TKIs with drugs in the glitazone class, anti-diabetic drugs that are agonists of the peroxisome proliferator-activated receptor-γ (PPARγ). Results were published online ahead of print in Nature.

Using cells from a cohort of 29 chronic phase CML patients, the researchers showed that combining imatinib with pioglitazone decreased the number of colony-forming cells sixfold (P < .0001) compared with imatinib alone. A similar effect was seen on chronic phase CML long-term culture-initiating cells, and pioglitazone’s effect was stronger when imatinib was present; the same was true with second-generation TKI dasatinib as well as with rosiglitazone.

They also investigated the mechanism for this effect, and found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets, “which are key guardians of the quiescence and stemness of CML LSCs,” the authors wrote.

The concept was also tested in CML patients. Three patients, who had received uninterrupted imatinib therapy for between 4 and 6 years, received pioglitazone in addition. None of these patients had achieved CMR before this change in treatment.

The addition of pioglitazone resulted in CMR in all three patients. In one, CMR was achieved 10 months after pioglitazone introduction, and the patient remained in CMR for at least 56 months, 53 months after stopping the drug. In the second, CMR was achieved after 1 year of pioglitazone addition, and this was maintained for 32 months until the patient withdrew. And in the third, CMR was achieved after 6 months, and remained for at least 38 months (28 after stopping pioglitazone).

As a result, phase II clinical trials are underway. “Progressive erosion of cancer stem cell pools may prove ultimately achievable pharmacologically, bringing hope of obtaining cancer eradication in a variety of human malignancies by combination therapy,” the authors concluded.