Identification of specific drug sensitivities to eradicate leukemic stem cells
Acute myeloid leukemia (AML) is a form of blood cancer that is still difficult to cure. Survival rates on average have remained less than 30%. Older patients, who are at the greatest risk of developing AML, have especially poor survival and since we are living in a continuously ageing society, this results in a significant increase in both social as well as economic burden in the next decade(s). Therefore, better therapies against AML are clearly needed. Within the current proposal, the focus is on small molecules targeting the epigenome. Over the past years it has been shown that mutations frequently occur in enzymes that control the epigenome in AML, and indeed as a consequence the epigenome is altered in AML patients. However, work by this consortium and others has also shown that AML is a rather heterogeneous disease, whereby the spectrum of mutations that together give rise to AML can be rather patient-specific. Thus, a personalised approach will be needed. Janssen has identified promising leads that may result in better treatment options. These are small molecules target specific epigenetic regulatory processes.
As a continuation of a long-standing collaboration between the Schuringa lab at the UMCG (Groningen) and Janssen will exploit these potential leads as well as novel targets identified/validated by Janssen in detail, both in vitro as well as in vivo, making use of the preclinical humanized niche patient-derived xenograft models. The drug screens will be coupled to quantitative proteome screens in order to link drug sensitivities to specific genetic aberrancies and signaling networks. Ultimately, this study should result in the development of more curative patient-specific treatment options for AML patients.