Who We Are

Scientific Interest

One important hypothesis of our work states that epigenetic changes affect stemness of cancer cells and cause therapy resistance. Hence, epigenetic therapies may be an efficient approach to overcome therapy resistance (Figure 1).

We have identified a novel epigenetic therapy resistance mechanism in Acute Myeloid Leukemia (Figure 2). Importantly, therapy resistance can be tackled by proteasome inhibition (or HSP90 inhibition). A multicenter clinical trial is planned to evaluate this concept in relapsed and refractory AML patients.

Chromatin and histone modifications as therapeutic targets are a field of active investigation. In an international collaborative effort we took part in the identification of LSD1 as a suitable target for differentiation therapy in AML (Schenk et al., 2012). Currently, we are performing a phase I/II clinical trial to test this approach in patients with refractory AML  (NCT02261779). Biomarker analyses to identify why patients respond or do not respond are underway.

Alterations of DNA methylation occur frequently in most cancers. We are studying how changes in DNA methylation affect disease pathogenesis and therapy resistance in several cancer types. In genetic mouse models we are modeling leukemogenesis under conditions with increased or decreased DNA methyltransferase activity (Schulze et al., Blood 2016). In clinical trials we evaluate how DNA hypomethylating drugs such as Azacytidine can affect therapy response (Müller-Tidow et al., Leukemia 2016). 

Mechanisms of stemness and aggressive disease in leukemia and beyond. In a clinical trial we are evaluating whether a novel CXCR4 inhibitor, BL-8040, that targets leukemic stem cells can improve therapy outcome for patients in first clinical remission https://clinicaltrials.gov/show/NCT02502968 .

With clinical trial data we developed a patient specific score to predict older AML patient´s response to induction chemotherapy (Krug et al., 2010) https://www.iblood.de/aml/.

Recently, we identified a novel familial AML syndrome caused by germline DDX41 mutations (Figure 3) (Polprasat, Schulze et al., 2015).

These mutations predispose to AML, MDS and other hematological malignancies. We are currently investigating the pathogenetic mechanisms of mutations in the RNA helicase DDX41.

Non-coding RNAs are important mediators of disease aggressiveness. We discovered MALAT-1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) as a long non-coding RNA that is closely associated with lung cancer metastasis (Ji, Diederichs et al., 2003). Recently, we discovered that snoRNA functions are essential for leukemic stem cell self renewal in AML1-ETO induced leukemia (Figure 4)(Zhou et al., 2017). Currently, we are analyzing the specific functions of non-coding RNAs in leukemia and lung cancer.

Vacancies

We are always looking for outstanding postdocs, physician scientists and graduate students. If you are interested in our team, projects and research, please contact Carsten Müller-Tidow directly. Thank you very much!