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Andrew M. Brunner, M.D.
ATR Inhibition to Treat Patients with Progressive or Refractory Myelodysplastic Syndromes

Andrew M. Brunner, M.D.

Massachusetts General Hospital

2019 Funding recipient

ATR Inhibition to Treat Patients with Progressive or Refractory Myelodysplastic Syndromes

EvansMDS Young Investigator Award

PROJECT SUMMARY

Since my appointment as Instructor in Medicine at HMS, I have worked to provide outstanding clinical care for patients with MDS, including the development of a robust clinical trial portfolio and teaching residents and fellows about MDS and other blood cancers, while at the same time developing investigator initiated clinical trials and original research in outcomes to further advance the treatment of MDS. In the future, I hope to contribute as a nationally-recognized expert in the treatment of MDS to develop new and novel therapies. The EvansMDS Young Investigator Award will allow me to continue my work in a dynamic academic setting with laboratory and clinical collaborators, with a goal of identifying novel new approaches that will change the treatment paradigm in MDS and provide better, more tolerable therapies that will improve the quality of life and survival of our patients.

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.