Research focus

The leukemia stem cell niche offers leukemia cells in the bone marrow special protection, e.g. from chemotherapy. The complex interactions between leukemia and stromal cells are only partially understood. Our research group aims to explore these complex interaction networks in order to identify new target structures for leukemia therapy. Our research focuses on acute myeloid leukemia. The great advantage of our research group is that we have access to material from the clinic's own AML biobank, in which bone marrow, blood and plasma samples from AML patients are collected. In addition, we are part of one of the leading AML study groups in Germany, which enables us to analyze our laboratory results directly in the context of clinical data. In particular, we often work on projects to improve leukemia therapy in close cooperation with the pharmaceutical industry. Our current projects focus on the importance of stem cell-relevant signaling pathways in the leukemia stem cell niche, the influence of a hypoxic environment within the bone marrow and new aspects of immunotherapy for the treatment of AML. By co-culturing AML cells with bone marrow stromal cells (endothelial cells and osteoblasts) and subsequent gene expression analysis, we were also able to identify further genes that could be important in the interaction between AML and stromal cells in the bone marrow niche. Some of these genes showed prognostic relevance for the survival of AML patients, which is why we are currently conducting detailed investigations into their pathophysiological significance. A selection of current projects is briefly presented below.

Single projects

Analysis of the Hedgehog signaling pathway in AML
One of our projects deals with the role of the Hedgehog signaling pathway in acute myeloid leukemia. We were able to demonstrate a prognostic relevance for the Hedgehog transcription factors GLI in AML, whereby the activation of the signaling pathway presumably results from a paracrine interaction with bone marrow stromal cells. In addition, specific GLI inhibition mediated anti-leukemic effects in vitro and in vivo (Wellbrock et al, Clin Cancer Res 2015;21(10)). In further studies, we were able to demonstrate the interaction of GLI with other signaling cascades such as the FLT3 and PI3K axis or the BET protein BRD4 (Latuske et al, Oncotarget 2017;8(17); Wellbrock et al, Ann. Hematol. 2021;100(12)). Our experiments on the anthelmintic mebendazole are particularly interesting: we were able to show that mebendazole is also a potent GLI inhibitor, which promotes the proteosomal degradation of GLI proteins (Freisleben et al, Int J Mol Sci 2021;22(19)). In the near future, we will initiate a Phase I clinical trial for the treatment of AML patients with mebendazole, which will include an accompanying experimental program with which we want to decipher the underlying mechanisms of the GLI signaling cascade in AML in more detail.

Analysis of the importance of the immune checkpoint axis TIGIT in AML and other cancers
In recent years, immunotherapy has become the focus of cancer therapy (Couzin-Frankel, Science 2013; 342(6165)). Through the abnormal expression of cellular proteins, the immune system can recognize tumor cells as degenerated and eliminate them. However, the tumor develops strategies to evade this immune surveillance, a process known as tumor escape (Dranoff, Nature Reviews Cancer 2004(4); Finn, Annals of Oncology 2012(23)). Immune checkpoint molecules play a crucial role in immune escape. In the healthy organism, they regulate the delicate balance of activating and inhibitory signals of T cell activation, making them important factors in maintaining the immune system's self-tolerance. The inhibitory immune checkpoint receptors are expressed by T cells, their respective ligands by antigen-presenting cells, which leads to suppression of the immune response when binding to the immune checkpoint receptors on the T cells. Tumor cells make use of this mechanism by expressing immune checkpoint ligands. The best known representatives of immune checkpoint molecules are CTLA-4 and PD-1, and blocking antibodies against both molecules are approved for the treatment of various cancer entities. Our work focuses on a lesser known immune checkpoint axis, namely the immune checkpoint receptor TIGIT, which binds the ligands PVR and PVRL2 and can thus mediate an inhibitory signal. In recent years, we have been able to demonstrate by multiparametric flow cytometry that various immune cell populations such as T cells, NK cells but also tumor-associated macrophages from AML patients have a high expression of TIGIT and other immune checkpoint molecules. In functional assays, we were also able to show that blocking the TIGIT axis is a promising therapeutic option for AML patients (Stamm et al, Oncogene 2018;37(39); Brauneck et al, Oncoimmunology 2021;10(1); Brauneck et al, Int J Mol Sci 2021;22(23); Brauneck et al, JITC 2022;10(12)). In addition, we have investigated the importance of the TIGIT axis in other cancer entities such as multiple myeloma, breast cancer and ovarian cancer, where we were also able to demonstrate that the axis is particularly active and thus a promising target for immunotherapeutic approaches (Stamm et al, Oncoimmunology 2019;8(12); Brauneck et al, Front Med (Lausanne) 2021; Weimer et al, Cells 2022;11(6)). Among other things, we are currently working on identifying further immunotherapeutic targets that act synergistically with TIGIT blockade and could therefore lead to improved treatment options for AML patients in the long term.

Scientific collaborations outside the II. Department of Medicine

• Prof. Dr. Leticia Oliveira-Ferrer, Clinic and Polyclinic for Gynecology, University Medical Center Hamburg-Eppendorf
• Prof. Dr. Manfred Jücker, Dr. Sabine Windhorst, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf
• Dr. Kerstin Cornils, Prof. Dr. Ingo Müller, Clinic and Polyclinic for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf
• Dr. Stefan Horn, PD Dr. Kristoffer Riecken, Cell and Gene Therapy Research Department headed by Prof. Dr. Boris Fehse, Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf
• Prof. Dr. Julian Schulze zur Wiesch, I. Medical Clinic and Polyclinic (Gastroenterology with Infectiology and Tropical Medicine Sections), University Medical Center Hamburg-Eppendorf
• Prof. Dr. Friedrich Koch-Nolte, Prof. Dr. Friedrich Haag, Prof. Dr. Eva Tolosa, Institute of Immunology, University Medical Center Hamburg-Eppendorf
• Prof. Dr. Nicolaus Kröger, Prof. Dr. Francis Ayuk, Dr. Mathias Schäfersküpper, Interdisciplinary Clinic and Polyclinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf
• Prof. Dr. Ulrich Schüller, Institute for Neuropathology, University Medical Center Hamburg-Eppendorf
• Dr. Malte Kriegs, Prof. Dr. Kerstin Borgmann, Clinic and Polyclinic for Radiotherapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf
• Dr. Lennart Viezens, Clinic and Polyclinic for Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf
• Prof. Dr. Martin Horstmann, Research Institute Children's Cancer Center Hamburg

• Prof. Dr. Susanne Sebens, Institute for Experimental Tumor Research, Christian-Albrechts-Universität zu Kiel
• Prof. Dr. Cyrus Khandanpour, Dr. Hari Gorantla, Dr. Lorenz Oelschläger, Clinic for Hematology and Oncology, University Medical Center Schleswig-Holstein
• Prof. Dr. Michael Heuser, Prof. Dr. Felicitas Thol, Hannover Medical School
• Prof. Dr. Lars Bullinger, Hematology, Oncology and Tumor Immunology, Charité Berlin
• Dr. Vadim Sumbayev, Prof. Dr. Yuri Ushkaryov, Medway School of Pharmacy, University of Kent, UK
• APIS Assay Technologies Ltd. Citylabs 1.0 Nelson Street, Manchester, M13 9NQ
• Prof. Dr. Sebastian Wicha, AG Wicha, University of Hamburg, Department of Chemistry at the Institute of Pharmacy
• Prof. Dr. Jürgen Krauter, Chief Physician, Medical Clinic III, Braunschweig Municipal Hospital
• Dr. Andreas Sputtek, Medical Laboratory Bremen