With the recent identification of molecular pathways which contribute to MDS pathogenesis, we can envision targeted therapies based on our improved fundamental understanding of the disease. It is already apparent that MDS is a molecularly heterogeneous disease with distinct outcomes. This is typified by the 5q- syndrome, which is associated with dramatic sensitivity to lenalidomide. Hypomethylating agents are another potential class of targeted therapies; it is possible that mutations in TET2
and methylation studies in MDS patient samples may provide insight into their therapeutic role in MDS. It will be interesting to see if patient response to decitabine or 5-azacitidine can eventually be correlated to specific mutations or methylation profiles. Although we do not yet have agents directed at specific transcription factors affected in MDS, therapies affecting transcription are being actively pursued in clinical trials. Histones integrate multiple epigenetic signals to regulate transcription, and one class of agents being intently studied is those affecting histone modification. As a class, the histone deacetylase inhibitors have been widely explored in phase I and II clinical trials.51
There is some early evidence that HDAC inhibitors alone or in combination with hypomethylating agents may have potential therapeutic benefit in MDS.52,53
Retinoic acid has also been tested as a potential therapy which can activate differentiation programs. Early reports suggest that it may have a benefit in the treatment of MDS related anemia in patients with low epo levels.54
Disrupted signaling pathways in MDS are also targets for therapy. Clinical trials with receptor kinase inhibitors, specifically FLT-3 inhibitors are actively being tested in patients with MDS and AML with RTK mutations and have shown some preliminary efficacy.55
Although Ras family members have been difficult to target, its downstream pathways may be amenable to manipulation. Inhibitors of downstream signaling components -- RAF, MEK, AKT, mTOR, etc. all serve as potential targets of therapy. In the subset of MDS and MDS/MPN patients with JAK2
mutations, JAK2 kinase inhibitors may be of benefit.56
Many of these agents are newly in development and we await results from ongoing clinical trials to determine the potential benefits from these targeted therapies.