Acute myeloid leukemia (AML) is a deadly blood cancer with a long-term survival below 30%. In last decades, treatment strategy has not changed substantially and consists of intensive chemotherapy and/or allogeneic stem cell transplantation. Novel targeted therapies exist and are very potent in the initial course of treatment, however, most patients unfortunately develop resistance. While it is widely accepted that turning oncogene-targeted therapeutics into curative therapies will require drug combinations, the pre-clinical and clinical development of rational combination therapies remains challenging at multiple levels.
In AML-SynergyX project, we focused on the FLT3 gene that is one of the most frequently mutated genes in AML and has been associated with high relapse rate and poor survival prognosis. Although specific inhibitors of mutated FLT3 are effective in the initial treatment, patients eventually develop the drug-resistant disease. We anticipate that by providing e will uncover new entry points for rational combination therapies that are urgently needed to turn the recent clinical success of FLT3 inhibitors into the cure.
Our work has identified a surface molecule CD70 as a top hit. CD70 is a member of the tumor necrosis factor (TNF) superfamily and the ligand for the cytokine receptor CD27. Interestingly, it has also been reported to be upregulated specifically on AML blasts and leukemia stem cells, but not on healthy stem cells, progenitors, or differentiated blood cells. Role of CD70 in the adaptation of leukemia cells has been described previously. In conclusion, while the project did not identify novel drug targets as initially hoped, it made significant contributions to the development of genetic screening tools, provided valuable insights into the transcriptional responses to FLT3 inhibition in AML, and supported the established role of CD70 as a potential target in AML.
