Characterization of the Mechanisms of Resistance to Azacitidine

Condition(s) studied

Study summary

Myelodysplastic syndromes (MDS) are frequent diseases in elderly patients (median age: 71 years). IPSS classification defines low risk (Low and Intermediate 1), and high risk (Intermediate 2 and High) MDS. High-risk MDS (MDS-HR) have a high risk of transformation into acute leukemia with multilineage dysplasia (AML-DML). The success of Azacitidine has been mainly achieved through a rigorous empirical and clinical research, but the molecular mechanisms by which this molecule exerts its effects remain poorly characterized. The primary mode of action of Azacytidine is through DNA demethylation, and integration in to mRNA that favor traduction inhibition. The impact of this molecule on various cell death programs involved in the elimination of leukemic cells : apoptosis and autophagy is currently poorly known.

The research program and clinical studies we proposed focus on two major aspects:

\- Main objective: Molecular mechanism of action and resistance to Azacitidine: Role of apoptosis versus autophagy.

\- Secondary Objective: Reversion of Azacytidine resistance using different drugs targeting apoptosis and/or autophagy. Our laboratory has identified new molecules to selectively induce different types of cell death (apoptosis or autophagy).

Eligibility

Primary outcome measure(s)

• hematological response — at 3 months
  Hematological response evaluated by the International Working Group (IWG) response of Cheson
• hematological response — at 6 months
  Hematological response evaluated by the International Working Group (IWG) response of Cheson

Trial sites (4)

More Centre Hospitalier Universitaire de Nice trials in France