Mass General Cancer Center Recruits Patients with MDS, CMML for Trial of Novel Drug
Key findings
- In preclinical research at the Massachusetts General Hospital Cancer Center, ATR kinase was shown to be critical for survival of cells associated with myelodysplastic syndrome that expressed a certain spliceosome mutation
- Application of ATR inhibitors to such cells induced DNA damage and cell death
- The Mass General Cancer Center is sponsoring a phase 1b trial of AZD6738, an investigational oral ATR kinase inhibitor, in patients with myelodysplastic syndrome or chronic myelomonocytic leukemia
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The Massachusetts General Hospital Cancer Center is sponsoring a phase 1b trial of AZD6738, an investigational oral ATR kinase inhibitor, in patients with myelodysplastic syndrome or chronic myelomonocytic leukemia. Currently in the recruitment stage, the study design is described in detail at ClinicalTrials.gov.
Lee Zou, PhD, associate scientific director of the Massachusetts General Hospital Cancer Center, and Timothy A. Graubert, MD, director of the Massachusetts General Hospital Hematologic Malignancy Program, and colleagues, describe the rationale for the trial in Oncotarget.
Targeting R-loop–Associated ATR Response
Many patients with hematologic malignancies have mutations in genes encoding components of the spliceosome, the cellular "machines" that aid in RNA splicing. In previous research, published in Molecular Cell, Dr. Zou and Dr. Graubert and colleagues demonstrated that one particular spliceosome mutation, U2AF1 S34F, induces R-loop accumulation.
R loops—transcription intermediates that contain an RNA:DNA hybrid and displaced single-stranded DNA—have useful physiologic functions, but aberrant levels can create genomic instability.
In further work published in Cancer Research, the Mass General Cancer Center researchers determined that regardless of where R-loops induce replication stress in the genome, ATR kinase was activated in cells that expressed U2AF1 S34F cells. Application of ATR inhibitors to such cells induced DNA damage and cell death.
R-loop–associated ATR response is thus a potential therapeutic target in patients who carry the U2AF1 S34F mutation. ATR, a serine/threonine protein kinase upregulated in a variety of cancer cell types, plays a key role in DNA repair, cell cycle progression and survival.
Details of the Trial
Adults who have recurrent, persistent or progressive MDS or chronic myelomonocytic leukemia are eligible for the clinical trial. All such patients are eligible for the dose-finding phase, but only patients who have a spliceosome mutation will be enrolled in the dose-expansion phase.
The primary outcomes of interest are safety and tolerability, but the investigators will also evaluate whether AZD6738 has any effect on tumor growth and patient survival. The trial was developed and is being led by Andrew Brunner, MD, a clinical investigator in the Mass General Center for Leukemia. AstraZeneca is the industry sponsor of the trial.
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