Translational brain tumor models
The focus of the group "Translational Brain Tumor Models" is preclinical translation. The analysis of primary brain tumors and development of novel pediatric brain tumor models enables the development of new therapeutic strategies that can be translated into clinical trials.
We apply molecular genetic, cell biology, and clinical analyses, as well as preclinical tumor models with the highest possible similarity to primary tumors, to identify therapeutic targets of pediatric brain tumors. We are using these findings to develop novel therapies that exploit the individual tumor's mechanism of action. These preclinical data provide the basis for the development of new clinical trials.
Our goal is therefore to better characterize them, to identify clinically relevant and distinct molecular subgroups as well as the genes and signaling pathways driving them, and, most importantly, to develop suitable human and murine model systems through which the various diseases and interactions can be recapitulated and which reflect the heterogeneous situation within a tumor. In addition, we are committed to finding new candidates for targeted therapies. Our goal is to translate findings from these genomic studies into novel strategies for optimal treatment of patients.
Novel drug targets, often in combination with established cytostatics and/or chemotherapeutics, are investigated using the model systems (cell lines, patient-derived orthotopic xenografts [PDX] and organoid cultures). The current focus of the group is on the targeted treatment of MYC (N)-driven brain tumors, SHH-driven medulloblastomas, PFA and RELA ependymomas, and ETMR tumors using a broad spectrum of drugs.
Spotlight - AG Milde
Clinical Trial Development
We are currently coming up with a new Spotlight for you and therefore ask for a little patience. However, we are working very closely with the KiTZ Clinical Trial Unit, for example, to transfer (pre-) clinically gained insights into clinical application. Until we tell you something more about our research group specifically, you can already find out there what we are working on.
Tumor Model Development
In the focus of tumor model development, we are working on the creation and testing of new in vitro and in vivo models of childhood brain tumor diseases. The goal is to represent childhood brain tumors in their broad diversity as accurately as possible so that drug discovery results can be better translated to the clinic. The focus is on model development of low-grade gliomas and high-grade tumors with genetic cancer predisposition (e.g., Li-Fraumeni medulloblastoma).
Signaling Biology and Tumor Microenvironment
In the focus of pathway biology and tumor microenvironment, we investigate the effects of targeted cancer therapies on activated tumor signaling pathways and the consequences for the interaction between tumor and surrounding (immune) cells. The goal is to understand information about the effects of targeted therapies on the immune system, and to exploit it therapeutically in the future. On the one hand, this knowledge may allow us in the future to better classify patients into risk groups before starting therapy, and thus to target therapy more effectively. On the other hand, it will allow us to develop new therapeutic concepts that target tumor cells and exploit the anti-tumor function of immune cells.
Preclinical Drug Development
The focus area Preclinical Drug Development is dedicated to the testing and confirmation of new compounds that can be used for the treatment of childhood brain tumors. For this purpose, the essential pre-clinical prerequisites (e.g. target expression, target dependence, on-target activity, blood-brain barrier mobility, etc.) are tested in order to increase the chances of success of translation into clinical application in the course of clinical studies.
Clinical Trial Development
Clinical Trial Development focuses on the translation of (pre-) clinical knowledge into clinical application. For example, we develop molecular risk stratifications in order to treat patients with medulloblastoma in a risk-appropriate manner in the SIOP medulloblastoma studies. On the other hand, we are involved in the development of early phase I/II studies within the SIOP-LOGGIC studies in order to be able to treat patients with low-grade gliomas in a targeted and improved manner.
1. Martin Mynarek*, Denise Obrecht*, Martin Sill, Dominik Sturm, Katja Kloth-Stachnau, Florian Selt, Jonas Ecker, Katja von Hoff, Björn-Ole Juhnke, Tobias Goschzik, Torsten Pietsch, Michael Bockmayr, Marcel Kool, Andreas von Deimling, Olaf Witt, Ulrich Schüller, Martin Benesch, Nicolas U Gerber, Felix Sahm, David T W Jones, Andrey Korshunov, Stefan M Pfister, Stefan Rutkowski*, Till Milde*: Identification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts.
Acta Neuropathol. 2023 Jan;145(1):97-112. doi: 10.1007/s00401-022-02522-4. Epub 2022 Dec 2. PMID: 36459208
2. Jonas Ecker, Florian Selt, Dominik Sturm, Martin Sill, Andrey Korshunov, Steffen Hirsch, David Capper, Nicola Dikow, Christian Sutter, Carina Müller, Romain Sigaud, Angelika Eggert, Thorsten Simon, Tim Niehues, Andreas von Deimling, Kristian W Pajtler, Cornelis M van Tilburg, David T W Jones, Felix Sahm, Stefan M Pfister, Olaf Witt, Till Milde: Molecular diagnostics enables detection of actionable targets: the Pediatric Targeted Therapy 2.0 registry. Eur J Cancer. 2022 Nov 25;180:71-84. doi: 10.1016/j.ejca.2022.11.015. Online ahead of print. PMID: 36542877
3. Florian Selt, Romain Sigaud, Gintvile Valinciute, Philipp Sievers, Julia Zaman, Clara Alco, Simone Schmid, Heike Peterziel, Jessica W Tsai, Romain Guiho, Juan Pedro Martínez-Barbera, Stefan Pusch, Jing Deng, Yifan Zhai, Cornelis M van Tilburg, Martin U Schuhman, Ahmed E L Damaty, Pratiti Bandopadhayay, Christel Herold-Mende, Andreas von Deimling, Stefan M Pfister, Joan Montero, David Capper, Ina Oehme, Felix Sahm, David T W Jones, Olaf Witt, Till Milde: BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma.
Neuro Oncol. 2022 Aug 17:noac199. doi: 10.1093/neuonc/noac199. Online ahead of print. PMID: 35977048
4. Romain Sigaud*, Lisa Rösch*, Charlotte Gatzweiler*, Julia Benzel*, Laura von Soosten*, Heike Peterziel, Florian Selt, Sara Najafi, Simay Ayhan, Xenia F Gerloff, Nina Hofmann, Isabel Büdenbender, Lukas Schmitt, Kathrin I Foerster, Jürgen Burhenne, Walter E Haefeli, Andrey Korshunov, Felix Sahm, Cornelis M van Tilburg, David T W Jones, Stefan M Pfister, Deborah Knoerzer, Brent L Kreider, Max Sauter*, Kristian W Pajtler*, Marc Zuckermann*, Ina Oehme*, Olaf Witt*, Till Milde*: The first-in-class ERK inhibitor ulixertinib shows promising activity in MAPK-driven pediatric low-grade glioma models.
Neuro Oncol. 2022 Jul 27:noac183. doi: 10.1093/neuonc/noac183. Online ahead of print. PMID: 35882450
5. Jonas Ecker, Venu Thatikonda, Gianluca Sigismondo, Florian Selt, Gintvile Valinciute, Ina Oehme, Carina Müller, Juliane L Buhl, Johannes Ridinger, Diren Usta, Nan Qin, Cornelis M van Tilburg, Christel Herold-Mende, Marc Remke, Felix Sahm, Frank Westermann, Marcel Kool, Robert J Wechsler-Reya, Lukas Chavez, Jeroen Krijgsveld, Natalie Jäger, Stefan M Pfister, Olaf Witt, Till Milde: Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma.
Neuro Oncol. 2021 Feb 25;23(2):226-239. doi: 10.1093/neuonc/noaa191. PMID: 32822486
6. Diren Usta, Romain Sigaud, Juliane L Buhl, Florian Selt, Viktoria Marquardt, David Pauck, Jennifer Jansen, Stefan Pusch, Jonas Ecker, Thomas Hielscher, Johanna Vollmer, Alexander C Sommerkamp, Tobias Rubner, Darren Hargrave, Cornelis M van Tilburg, Stefan M Pfister, David T W Jones, Marc Remke, Tilman Brummer, Olaf Witt, Till Milde: A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF-driven Pediatric Low-Grade Glioma Cells.
Mol Cancer Ther. 2020 Aug;19(8):1736-1750. doi: 10.1158/1535-7163.MCT-19-1021. Epub 2020 May 25. doi: 10.1158/1535-7163.MCT-19-1021. PMID: 32451331
7. Juliane L. Buhl, Florian Selt, Thomas Hielscher, Romain Guiho, Jonas Ecker, Felix Sahm, Johannes Ridinger, Dennis Riehl, Diren Usta, Britta Ismer, Alexander C. Sommerkamp, J.P. Martinez-Barbera, Annika K. Wefers, Marc Remke, Daniel Picard, Stefan Pusch, Jan Gronych, Ina Oehme, Cornelis M. van Tilburg, Marcel Kool, Daniela Kuhn, David Capper, Andreas von Deimling, Martin U. Schuhmann, Christel Herold-Mende, Andrey Korshunov, Tilman Brummer, Stefan M. Pfister, David T.W. Jones, Olaf Witt, Till Milde: The senescence-associated secretory phenotype mediates oncogene-induced senescence in pediatric pilocytic astrocytoma.
Clin Cancer Res, 25 (6), 1851-1866 2019 Mar 15. PMID: 30530705
8. Florian Selt, Juliane Hohloch, Thomas Hielscher, Felix Sahm, David Capper, Andrey Korshunov, Diren Usta, Sebastian Brabetz, Johannes Ridinger, Jonas Ecker, Ina Oehme, Jan Gronych, Viktoria Marquardt, David Pauck, Heidi Bächli, Charles D. Stiles, Andreas von Deimling, Marc Remke, Martin U. Schuhmann, Stefan M. Pfister, Tilman Brummer, David T.W. Jones, Olaf Witt, Till Milde: Establishment and application of a novel patient-derived KIAA1549:BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing.
Oncotarget. 2017 Feb 14;8(7):11460-11479. doi: 10.18632/oncotarget.14004. PMID: 28002790
Team members
- Prof. (apl.) Dr. med. Till Milde, MHBA (Grroup leader)
- Dr. Romain Sigaud, PhD (Post-Doc)
- Dr. rer. nat. Anna Kolodziejczak, PhD (Post-Doc)
- Dr. med. Florian Selt, MD (Physician-Scientist)
- Dr. med. Jonas Ecker, MD (Physician-Scientist)
- Dr. med. Diren Usta (Physician-Scientist)
- Raquel Carvalho (Project manager)
- Daniela Kocher, M.Sc. (PhD student)
- Nora Jamalladin, M.Sc. (PhD student)
- Johanna Vollmer (PhD student)
- Simon Zeuner (PhD student)
- Leo Nonnenbroich (PhD student)
- Pauline Becker (PhD student)
- Carina Konrad (Technical assistant)
