PD Dr. Ina Oehme
Group leader "Functional Studies"
German Cancer Research Center
CCU Pediatric Oncology / G340
Im Neuenheimer Feld 280
For differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors are of particular interest. HDAC inhibitors are currently under investigation for the treatment of a broad spectrum of cancer diseases. However, one clinical drawback is class-specific toxicity of unselective inhibitors, limiting their full anti-cancer potential. Selective targeting of individual HDAC isotypes in defined tumor entities may therefore be an attractive alternative treatment approach.
We have identified HDAC family member 8 (HDAC8) as a novel target in childhood neuroblastoma. The development of neuroblastoma, the most common extracranial solid tumor in children, is hypothesized to be related to maturation defects of neural crest derived precursor cells of the peripheral sympathetic nervous system. The long-term overall survival probability of high-risk neuroblastoma patients is less than 50%.
Inhibition of HDAC8 enzymatic activity with selective inhibitors exhibits anti-neuroblastoma activity. Selective HDAC8 inhibition leads to cell cycle arrest and differentiation in vitro and in vivo. Upon combination with retinoic acid, differentiation is enhanced. Thus, selective HDAC targeting can be effective in tumors exhibiting HDAC isotype dependent tumor growth and can be combined with differentiation-inducing agents. Future investigations will focus on the use of selective HDAC8 inhibitors as anti-neuroblastoma drugs on the one hand; on the other hand, we will use the selective inhibitors as a tool to further understand the mechanistic background of HDAC8 mediated malignancy of neuroblastoma. In addition, we will investigate cooperating signaling pathways using synthetic lethal screening approaches.
Autophagy is a cytoprotective mechanism that may help advanced cancer cells survive stressful conditions such as chemotherapy. We identified HDAC family member 10 (HDAC10) as a promoter of autophagy-mediated survival in neuroblastoma cells and propose this HDAC isotype as a druggable regulator of advanced-stage tumor cell survival. These results propose a new and promising way to considerably improve treatment response in patient subgroups with autophagy-dependent therapy resistance.
Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g. via bioreactor systems, through which culture medium is constantly pumped at a flow rate reflecting physiological conditions. In this project, we apply both static 3D growth and 3D growth within a bioreactor system modulate and investigate key hallmarks of cancer cells, including proliferation and cell death as well as macroautophagy, a recycling pathway often activated by highly proliferative tumors to cope with metabolic stress.
The main focus of our co-clinical trial unit is translational research from bench to bedside and back with the aim to establish personalized targeted treatment concepts. Within the INFORM precision medicine registry study we generated a molecular diagnostics platform within the German Society for Pediatric Oncology and Hematology (GPOH) which enables us to identify therapeutic targets, biological tumor classifications and hereditary predisposition syndromes.
However, therapeutic targets with a high evidence for a therapeutic response (genetical driver mutations) are only detected in a rather small part of the tumors. Thus, there is urgent need to complement the molecular analyses by functional information derived from vital tumor cells. Our aim is to establish two-dimensional and three-dimensional in vitro cell cultures reflecting the heterogeneity and individuality of each tumor. These short term tumor cell cultures are subject to small molecule screening to generate a sensitivity profile of every individual tumor toward a large number of compounds. Putative synergistic actions are analysed for combinations of two or more compounds. Further analyses such as genetic characterization of the tumor samples (identification of biomarkers, CRISPR/CAS screenings, single cell sequencing) are performed in parallel settings. Our steadily growing repertoire of preclinical (patient-derived and genetic) mouse models (KiTZ cooperations) will allow us to subsequently assess the in vivo applicability of therapy options identified by our in vitro studies.
Ridinger J, Koeneke E, Kolbinger FR, Koerholz K, Mahboobi S, Hellweg L, Gunkel N, Miller AK, Peterziel H, Schmezer P, Hamacher-Brady A, Witt O, and Oehme I (2018) Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance. Sci Rep. 2018 Jul 3;8(1):10039.
Kolbinger FR, Koeneke E, Ridinger J, Heimburg T, Müller M, Bayer T, Sippl W, Jung M, Gunkel N, Miller AK, Westermann F, Witt O, Oehme I (2018) The HDAC6/8/10 inhibitor TH34 induces DNA damage mediated cell death in human high-grade neuroblastoma cell lines. Arch Toxicol. 2018 Aug;92(8):2649-2664.
Shen J, Najafi S, Stäble S, Fabian J, Koeneke E, Kolbinger FR, Wrobel J, Meder B, Distel M, Heimburg T, Sippl W, Jung M, Peterziel H, Kranz D, Boutros M, Westermann F, Witt O, Oehme I (2018) A kinome-wide RNAi screen identifies ALK as a target to sensitize neuroblastoma cells for HDAC8-inhibitor treatment. Cell Death & Differentiation. Dec; 25(12): 2053–2070.
Bingel C, Koeneke E, Ridinger J, Bittmann A, Sill M, Peterziel H, Wrobel JK, Rettig I, Milde T, Fernekorn U, Weise F, Schober A, Witt O, Oehme I (2017) Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance. Cell Death Dis 8: e3013.
Rettig I, Koeneke E, Trippel F, Mueller WC, Burhenne J, Kopp-Schneider A, Fabian J, Schober A, Fernekorn U, von Deimling A, Deubzer HE, Milde T, Witt O, Oehme I (2015) Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation. Cell Death Dis 6: e1657.
Oehme I, Linke JP, Böck BC, Milde T, Lodrini M, Hartenstein B, Wiegand I, Eckert C, Roth W, Kool M, Kaden S, Gröne HJ, Schulte JH, Lindner S, Hamacher-Brady A, Brady NR, Deubzer HE, Witt O. (2013) Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc Natl Acad Sci U S A 110(28): E2592-2601.
Oehme I, Lodrini M, Brady NR, Witt O (2013) Histone deacetylase 10-promoted autophagy as a druggable point of interference to improve the treatment response of advanced neuroblastomas. Autophagy 9(12):2163-2165.
Oehme, I., Deubzer, H. E., Wegener, D., Pickert, D., Linke, J. P., Hero, B., Kopp-Schneider, A., Westermann, F., Ulrich, S. M., von Deimling, A., et al. (2009). Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res 15, 91-99.