Project 1: Molecular determinants of decitabine responsiveness

Timothy Ley, MD, and John Welch, MD, PhD

The long term goal of this project is to better define treatment approaches for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

Using whole genome sequencing, we have found that these two diseases are caused by mutations in several shared genes. However, we do not know which mutations (or combinations of mutations) predict sensitivity or resistance to specific drugs.

Decitabine is one of the few drugs that both AML and MDS patients respond to, and it is one of the best tolerated AML drugs; it can be given to outpatients, unlike most AML chemotherapy. Approximately 30% of AML and MDS patients will respond to decitabine, but we do not know who will respond or why. We will use state-of-the-art genomic analyses to determine whether molecular signatures (mutations or changes in gene expression levels) correlate with response or resistance to decitabine.

Patients will be enrolled on a clinical trial and treated with the current, optimal regimen of decitabine (20 mg/m2/day for 10 consecutive days every 28 days). We will use exome sequencing to identify the key AML-causing mutations in each patient, and we will use expression profiling to determine the level of expression of all genes. We will correlate these results with clinical outcomes to identify molecular signatures of response and resistance. Further, we will track the percent of bone marrow cells carrying each of these mutations during the first 2 months of therapy, and determine whether the early clearance of mutations can rapidly identify the best responders.

As part of this project, it is our aim to build a pipeline for rapid, comprehensive genomic analysis that could be applied to other diseases and drugs, so that we can better tailor therapeutic choices for individual patients.