by ecancer reporter Janet Fricker

Adding pioglitazone, a glitazone widely used for diabetes treatment, to imatinib enabled chronic myeloid leukaemia (CML) patients to remain disease free for nearly five years, report French investigators in Nature.

CML is a myeloproliferative disorder resulting from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL.

While imatinib and other tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes for CML patients, fewer than 10% achieve complete molecular response, defined as the point where BRC-ABL transcripts are undetectable in blood.

Such failure has resulted from the inability of TKIs to eradicate quiescent (dormant non cycling) CML leukaemia stem cells.

The study by Philippe Leboulch, from CEA, Fontenay-aux-Roses, France, and colleagues ,showed that pioglitazone could block the molecular pathway leading to cell dormancy, which is thought to involve PPARy, STAT5, HIF2α and the protein CITED2.

The investigators went on to show that when pioglitazone was given temporarily to three CML patients with chronic residual disease despite continuous treatment with imatinib, all achieved sustained CMR for up to 4.7 years after pioglitazone withdrawal.

The data provided a strong rationale for a phase II clinical trial, which started in July 2009.

“This (the study) suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool,” write the authors.

In an accompanying commentary, Tessa Holyoake and David Vetrie, from the University of Glasgow, suggested that the cells are “probably either killed directly or driven to exit quiescence, which may lead to their eradication by [imatinib].”

They wrote, “Collectively, these results strengthen the concept that cancer stem cells exhibit vulnerabilities in otherwise normal molecular pathways that may be targeted in a selective manner to obtain a cure.”

Using drugs that have already been approved for other purposes, they added, can shorten the drug-development pathway by five to 10 years and reduce risks and costs.

Reference

S Prost, F Relouzat, M Spentchian, et al. Erosion of the chronic myeloid leukaemia stem cell pool by PPARy agonists. Nature.

T Hollyoake &. D Vetrie. Cancer: Repositioned to kill stem cells. Nature. 2015.