Combination therapies with the LSD1 inhibitor GSK2879552 for the treatment of T-cell acute lymphoblastic leukemia

01 October 2016 → 31 March 2017
Funding by bilateral agreement (private and foundations)
Research disciplines
  • Medical and health sciences
    • Pediatrics and neonatology
    • Pediatrics and neonatology
    • Nursing
    • Pediatrics and neonatology
Project description

Although the cure rates for patients with T-cell acute lymphoblastic leukemia (T-ALL) have gradually increased over the past decades, there is still a high need for more effective and less toxic drugs. Especially early T-cell precursor lymphoblastic leukemia (ETP-ALL), a new and aggressive subclass of T-ALL, has a poor response to current chemotherapy and a significant higher incidence of induction failure and hematological relapse. We recently have found that ETP-ALL is characterized by a high expression of the transcription factor ZEB2. Moreover, the generation of a novel conditional Zeb2 knock-in mouse model demonstrated that ZEB2 is a true driver for early T-ALL. Via pull down and mass spec experiments, the lysine specific demethylase LSD1 was identified as an interaction partner of ZEB2. This finding could be therapeutically exploited via LSD1 inhibition. Indeed, human T-ALL cell lines with ZEB2 expression were sensitive to the LSD1 inhibitor GSK2879552. Interestingly, also some cell lines with no expression of ZEB2 responded to the treatment indicating that LSD1 inhibition could be used for the treatment of a broader panel of T-ALLs. In this project, we would like to elucidate the pathways that are affected by LSD1 inhibition via RNA-sequencing. To increase the efficacy of LSD1 inhibition and to avoid the emergence of resistance, we will look for successful combination therapies. Both combinations with conventional chemotherapeutics and targeted agents will be tested in vitro and in vivo.