Project 4: Targeting ATR in TP53-mutated MDS/AML

Project 4 Co-leaders:

Geoffrey Uy, MD, PhD; (WashU) (Clinical Co-Leader)

Daniel C. Link, MD; (WashU) (Basic Science Co-Leader)

Mutations of TP53 are found in a significant percentage of cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). These mutations have a negative impact on prognosis, and standard therapies have limited effectiveness. Hypomethylating agents have shown some therapeutic activity, but complete mutation clearance is rare, leading to relapse. Our research suggests that TP53-mutated cells are sensitive to the combination of decitabine (a hypomethylating agent) and an ATR inhibitor (see figure). The study aims to characterize the therapeutic potential of this combination and investigate the underlying molecular mechanisms. In Aim 1, we will perform a clinical trial of an ATR inhibitor in combination with decitabine for patients with AML or MDS carrying TP53 mutations. Aim 2 will determine mechanisms by which this drug combination is selectively active in TP53-mutated AML/MDS. The ultimate goal is to provide evidence of safety, target engagement, and efficacy to support further clinical trials. Additionally, the molecular studies may reveal new insights into the sensitization of AML cells and identify potential new targets for treatment.