Andrew M. Brunner, M.D.
2019 Funding recipient
ATR Inhibition to Treat Patients with Progressive or Refractory Myelodysplastic Syndromes
EvansMDS Young Investigator Award
Current therapies for myelodysplastic syndromes (MDS) are limited; recurrently mutated genes in MDS may be avenues for new treatment options. Mutations in pre-mRNA splicing (most frequently U2AF1, SRSF2, and SF3B1) occur frequently in MDS and appear to be early events in the founding clones of disease. Recently, we showed that altered splicing results in increased R loops – DNA:RNA hybrids – during DNA replication. Resolution of R loops is necessary to avoid DNA replication fork collapse during DNA replication. R-loop resolution is dependent upon signaling through the serine-threonine kinase Ataxia telangiectasia and Rad3-related (ATR). Inhibition of ATR therefore is an appealing strategy in MDS, specifically in patients whose MDS harbors a splicing factor mutation.
The research supported by the EvansMDS YIA has three aims. First, I have the role of overall principal investigator in leading a multicenter phase 1b study of a specific ATR inhibitor, AZD6738, in patients with progressive MDS or chronic myelomonocytic leukemia (CMML). This is a study protocol which I wrote and which enrolls patients with both lower and higher risk MDS and CMML, who have progressed on initial therapy, to evaluate the safety and early indicators of efficacy of ATR inhibition in this disease. In addition to evaluating safety and overall efficacy, we are particularly interested in whether this agent will be active in cancers harboring mutations in the spliceosome. So far, patients have been enrolled to the first part of the study for both higher risk MDS (n=6) and lower risk MDS (n=2). No DLTs were seen in the first 6 patients with higher-risk MDS and this group is now enrolling to the part 2 expansion of up to 40 patients total.
The second and third aims pertain specifically to understanding and predicting response to treatment. As patients are enrolled, correlative samples will be collected and analyzed both for changes in clonal structure, using DNA sequencing techniques, during treatment, as well as evaluating on-target markers of ATR inhibition as a predictor of patient responses. For the second aim, we are collecting blood and marrow samples during treatment, and I will be correlating changes in clonal composition with patient responses. For the latter, ATR inhibition results in an increased DNA damage response; a bone marrow sample is collected on day 3 of treatment and stained for markers of ATR inhibition including pCHK1 and gH2AX. I am working to correlate the intensity of staining with response, with the hypothesis that increased DNA damage is more likely to be associated with treatment response. Samples are currently being collected for analysis; the IHC assay for ATR engagement has been validated in banked MDS patient samples.
Andrew M. Brunner, M.D., David P. Steensma, M.D., Targeting Aberrant Splicing in Myelodysplastic Syndromes: Biologic Rationale and Clinical Opportunity, Hematology/Oncology Clinics of North America 2020, DOI: 10.1016/j.hoc.2019.10.003.