Adding Pioglitazone to Imatinib May Improve Treatment of Chronic Myeloid Leukemia

the ONA take:

Patients with chronic myeloid leukemia (CML) who received imatinib plus pioglitazone, a drug commonly used to treat type 2 diabetes, achieved a sustained complete molecular response for up to 4.7 years after the withdrawal of the antidiabetes medication, a recent study published online in the journal Nature has shown.

For the study, Philippe Leboulch, MD, PhD, from Brigham & Women’s Hospital and Harvard Medical School Genetics Division in Boston, Massachusetts, and colleagues temporarily treated three patients with CML in chronic residual disease despite continuous treatment with imatinib with pioglitazone. When pioglitazone activates PPARγ, the expression of STAT5, HIF2α and CITED2 is decreased. These downstream signaling targets play a role in the CML leukemia stem cells that tyrosine kinase inhibitors such as imatinib may fail to eradicate.

"When pioglitazone was given temporarily to three chronic myeloid leukemia patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained complete molecular response, up to 4.7 years after withdrawal of pioglitazone," the authors write.

"This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool."

Imatinib is already approved by the US Food and Drug Administration (FDA) for the treatment of adult and pediatric patients with newly diagnosed Philadelphia chromosome positive CML in chronic phase, as well as those in blast phase, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

Erosion of the chronic myeloid leukaemia stem cell pool by PPAR[ggr] agonists : Nature : Nature Publ
Erosion of the chronic myeloid leukaemia stem cell pool by PPAR[ggr] agonists : Nature : Nature Publ
Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph+: t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. 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. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-[ggr] (PPAR[ggr]). We found that activation of PPAR[ggr] by the glitazones decreases expression of STAT5 and its downstream targets HIF2[agr] and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.
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