Maria (Ken) Figueroa, M.D.
2014 Grant Recipient
Epigenetic Determinants of Response to DNA Methyltransferase Inhibitors
Basic Science Research Grant 2014
The genetic material, or DNA, of a cell is full of instructions of how a cell and an organism should grow, develop, reproduce and even die. However, this information needs to be organized so that it can be used appropriately. The ability of a cell to access this information and release it in a controlled manner is contained in an additional layer of information, known as “epigenetic regulation”. This epigenetic information is encoded in a series of chemical modifications of the cell’s DNA and its associated proteins, and serves to determine which genetic program is turned on at any specific time. Myelodysplastic syndromes (MDS) are a series of blood disorders that cause profound dysfunction of the bone marrow, leading ultimately to bone marrow exhaustion or transformation to acute leukemia. MDS display profound abnormalities in the pattern of DNA methylation, a critical epigenetic modification, and to date the only drugs that have been demonstrated to improve the clinical outcome of MDS patients are those that target DNA methylation. Moreover, many patients with MDS carry mutations in genes that control the placement of DNA methylation and other epigenetic modifications. While azacytidine and decitabine, two epigenetic drugs that target DNA methylation, have improved the clinical outcome for some patients with MDS, most patients fail to respond. To this date it is unclear why some patients respond to these agents while others don’t. Moreover, it is currently impossible to predict at the time of diagnosis which patients will respond and which will prove resistant to this therapy. Furthermore, a minimum of 6 months are required before a patient can be deemed resistant to these drugs; therefore, a large fraction of patients must endure months of therapy with low chances of success before they can be offered alternative therapies. It is therefore imperative that we develop methods to accurately identify at the time of diagnosis those MDS patients who will respond to epigenetic therapies so that we can better risk-stratify them and early on offer alternative therapies to those patients with low chances of success. Moreover, we currently do not understand how or why resistant patients fail to respond to these drugs, a fact that significantly limits our ability to develop alternative therapies that can overcome this resistance. In the current study we propose to use state-of-the art sequencing technologies to fully interrogate the epigenetic profiles of 100 MDS patients treated with azacytidine and use computational and experimental approaches to address the following questions:
- Can we identify specific epigenetic characteristics that will help us to identify early on which patients will respond to epigenetic therapies and which will not?
- How does epigenetic deregulation contribute to resistance in those patients who fail to respond?
- Can we identify novel therapeutic targets that can be harnessed to overcome this resistance?
We expect that through the current proposal we will identify an epigenetic signature predictive of response to azacytidine treatment in MDS and gain a broader understanding of the mechanisms of sensitivity and resistance to this class of drugs. These studies will provide the groundwork for the design of novel treatments targeting mechanisms of resistance to these drugs, which will hopefully impact the large proportion of patients who do not respond to these agents, as well as the responders once they have inevitably developed resistance.