IDMIT (UMR-1184)

• Functional and therapeutic impact of PPARy in acute and chronic myeloid neoplasia: from biology to the clinic.
• Clinical research for targeted therapy

• Targeted therapy
• Alternative therapy
• Precision medicine

Scientific

• 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 alone to eradicate quiescent CML leukaemia stem cells (LSCs). 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-gamma (PPARgamma). This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.
• Myelofibrosis (MF) is a non-BCR-ABL myeloproliferative neoplasm associated with poor outcomes. Current treatment has little effect on the natural history of the disease. MF results from complex interactions between (a) the malignant clone, (b) an inflammatory context, and (c) remodeling of the bone marrow (BM) microenvironment. Each of these points is a potential target of PPARgamma activation. Here, we demonstrated the therapeutic potential of PPARgamma agonists in resolving MF in 3 mouse models. We showed that PPARgamma agonists reduce myeloproliferation, modulate inflammation, and protect the BM stroma in vitro and ex vivo. Activation of PPARgamma constitutes a relevant therapeutic target in MF, and our data support the possibility of using PPARgamma agonists in clinical practice.

Medical

• In the ACTIM phase 2 clinical trial, we asked whether pioglitazone add-on therapy to imatinib would impact CML residual disease, as assessed by BCR-ABL1 transcript quantification (NCT02888964).
• In the Second STOP After Pioglitazone Priming in CML Patients (PIO2STOP) phase 2 clinical trial, the study objectives are :

A. To assess safety and pharmacokinetics of the combination of PIO and TKI in CML subjects who experience a loss of MMR following a first TKI discontinuation, 

B. To assess survival without loss of MMR over a 12 months period following a second TKI discontinuation in subjects who achieve or maintain < MR4.5 with the combination PIO and TKI administered for at least 6 months. (NCT02889003). 

• In ACTIW phase 2 clinical trial the study objectives are to assess candidate therapies in combination or sequentially with Tyrosine Kinase Inhibitors in Chronic Phase-chronic Myelogenous Leukemia Patients in CCR Without Achieving a Deep Molecular Response. (NCT02767063).

Primary objective: to select molecules in combination or sequentially with imatinib, nilotinib, dasatinib, bosutinib or ponatinib potentially able to produce a 25% increase in the Cumulative Incidence of MR4.5 as compare to control.

• Acute Leukemia French Association (ALFA)