Current Projects

1. Mechanistic and functional dissection of early resistance to epigenetic inhibitors in Acute Myeloid Leukemia (Else-Kröner-Fresenius-Stiftung “First Grant”)

Drugs targeting epigenetic modifications are promising therapies in Acute Myeloid Leukemia (AML). However, early clinical trials with compounds targeting epigenetic modifiers as single agents suggest considerable non-genetic resistance, anticipatory combination treatments becoming pivotal for better and longer disease responses. In this project, we demonstrate, track and overcome routes of AML adaptation to inhibitors of the exemplary critical transcriptional regulators termed bromodomain and extraterminal (BET) proteins.

 

 

 

Project 2: Rational p300/CREBBP KAT inhibition in AML (DFG “Emmy-Noether-Program”)

With this project, we propose that the successful clinical introduction of novel enzymatic p300/CREBBP lysine acetyltransferase (KAT) inhibitors for treating AML requires a thorough, integrative and dynamic characterization of their actions and limitations in both naïve and resistant settings. Moreover, mechanistic treatment combination strategies are required to discern between non-discriminatory increased toxicity, prevention of resistance and induction of new vulnerabilities. Additionally, we aim to demonstrate that a continuous modeling of routes and stages of resistance to epigenetic modulators is likewise an unanticipated model of treatment in AML. Considering that non-genetic resistance to treatment induces new epigenetic/transcriptional landscapes, we speculate that the rational utilization of p300/CREBBP KAT inhibitors in a sequential mechanistic combination with other epigenetic inhibitors can guide treatment trajectories in AML by gradually decreasing plasticity.

Project 3: Cohesin deficiency and myeloid expansion: from mechanisms of action to novel therapeutic routes (UMC Mainz “High Potentials Grant”)

Loss-of-function mutations in members of the cohesin complex are recurrent events in myelodysplastic neoplasms (MDS) and acute myeloid leukemias (AML). Recently, convincing evidence has shown that cohesin deficiency leads to transcriptional dysregulation in hematopoiesis. Our preliminary data also suggest cohesin deficient cells to induce specific routes of transcriptional activation that cause myeloid disease progression. With this project, we evaluate causes and paths of cohesin deficiency-associated myeloid proliferation, both in normal hematopoiesis and in models of MDS and AML to identify opportunities to prevent myeloid cancer progression.