Project 3: Targeted therapy for splicing factor-mutant myeloid malignancies

Project 3 Co-Leaders:

Matthew Walter, MD (Wash U) (Basic Science Co-Leader)

Timothy Graubert, MD (MGH) (Clinical Co-Leader)

The long-term goal of this project is to develop novel therapies that exploit vulnerabilities induced by RNA splicing factor gene mutations in patients with myeloid neoplasms, including myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Preliminary results from our investigator-initiated clinical trial show that inhibiting ATR, a protein involved in DNA repair, using a single drug induces objective responses with acceptable toxicity in patients, but combination therapy will be required for more durable clinical benefit. This project will optimize the combination of ATR and PARP1 inhibition in preclinical models, providing a rationale for the next phase of clinical investigation.

Aim 1:

We will use multiple in vivo preclinical models to test the efficacy and safety of targeting both ATR and PARP1, another protein involved in DNA repair, in myeloid malignancies with splicing factor mutations. We will explore CHK1 inhibition as an alternative strategy to target the ATR signaling pathway.

Aim 2:

We will explore mechanisms of sensitivity and resistance to ATR inhibition using clinical samples, clinically relevant genetically-engineered mouse models, and gene-edited human leukemia cells.

The overall translational impact includes:

• providing preclinical proof of concept for dual targeting of ATR and PARP1 in myeloid malignancies with splicing factor mutations;
• developing a preclinical rationale for CHK1 inhibition as an alternative strategy to target ATR signaling;
• identifying biomarkers of sensitivity to ATR pathway inhibition, and
• understanding molecular mechanisms of resistance to ATR inhibition.