Epigenetic Modifications in Neuroblastoma – Novel Therapeutic Targets

from left to right: Jamie Hu, Johannes Fabian, Victoria Schmidt, Marie C. Schier, Marco Lodrini, Desirée Opitz Hedwig E. Deubzer, Markus Sohn, Theresa Thole, Jasmin Wünschel
© dkfz.de

Projects

Figure 1
© dkfz.de

Neuroblastoma is the most frequently occurring solid tumor in children. It originates from the sympathoadrenal lineage, which derives from neural crest cells, and belongs to the group of embryonic tumors. Surprisingly, many infants experience regression of their disease, even when metastasized, without or with only minimal therapy. However, older children frequently suffer from progressive metastasized disease.
Therapy of these high-risk neuroblastomas has remained difficult. Current multimodal treatment protocols include surgery, iodine-123 radiolabeled meta-iodo-benzylguanidine (I-123 MIBG) therapy, high-dose myeloablative regimens followed by autologous stem cell rescue and pulsed 13-cis retinoic acid in the post-consolidation phase. Despite dose intensification, only ~ 35% of children survive whereas the remaining patients die mostly from resistant relapses. In addition, current protocols not only cause acute toxicity but also result in long-term complications, which affect as many as ~ 40% of the survivors. This scenario necessitates both, the identification of signal transduction pathways promoting neuroblastoma malignancy and the development of novel, less toxic therapeutic approaches targeting these pathways.

Figure 2
© dkfz.de

In recent years, epigenetics has become an increasingly important aspect of cancer biology. In addition to blocking DNA methylation, inhibition of histone deacetylase (HDAC) activity has emerged as a promising strategy against both, leukemias and solid tumors. HDACs deacetylate both, nuclear histones and non-histone proteins such as transcription factors and thereby play fundamental roles in regulating numerous cellular processes (Figure 1). We have recently shown that the pan-HDAC-inhibitor Helminthosporium carbonum (HC)-toxin suppresses neuroblastoma malignancy in preclinical models at nanomolar concentration. The underlying mechanisms for the differentiation processes triggered by HDAC-inhibitors have not yet been elucidated. We aim to identify early master regulators of neuroblastoma cell differentiation using microarray platforms for genome-wide profiling of both messenger RNAs (mRNAs) and microRNAs (miRNAs) (Figure 2). In addition, we study the epigenetic regulation of master regulators with proven functional relevance in neuroblastoma biology (Figure 2).

Funding

- Bundesministerium für Bildung und Forschung (BMBF), Nationales Genomforschungsnetzwerk (NGFNplus), Extended Neuroblastoma Genome Interaction NEtwork (ENGINE)

- Heidelberg University „Exzellenziniative/Innovationsfond FRONTIER“

- Heidelberg University Olympia Morata Program

- Strategic Research Alliance BSP AG/DKFZ


Cooperation Partners

- Molecular Medicine Partnership Unit (MMPU) of Heidelberg University and EMBL

- Preclinical Target Development, Genomics and Proteomics Core Facilities (W150), DKFZ

- Department of Tumor Genetics (B030), DKFZ

- Clinical Cooperation Unit Neuropathology (G380), DKFZ

- Central Unit Biostatistics (C060), DKFZ

- Onco Lab, University of Essen

- Medizinisches Proteom Center, Ruhr University Bochum

- Transcriptome Analysis Laboratory, University of Goettingen

- Institute for Medical Virology, University of Frankfurt

- Department of Pediatric Hematology and Oncology, University of Cologne


Key references

- Deubzer HE, Schier MC, Oehme I, Lodrini M, Haendler B, Sommer A, Witt O. HDAC11 is a novel drug target in carcinomas. Int J Cancer. 2013 May 1;132(9):2200-8. doi: 10.1002/ijc.27876. Epub 2012 Oct 25.

- Milde T, Lodrini M, Savelyeva L, Korshunov A, Kool M, Brueckner LM, Antunes AS, Oehme I, Pekrun A, Pfister SM, Kulozik AE, Witt O, Deubzer HE. HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J Neurooncol. 2012 Dec;110(3):335-48. doi: 10.1007/s11060-012-0978-1. Epub 2012 Oct 6.

- Michaelis M, Kleinschmidt MC, Barth S, Rothweiler F, Geiler J, Breitling R, Mayer B, Deubzer HE, Witt O, Kreuter J, Doerr HW, Cinatl J, Cinatl J Jr. Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines. Biochem Pharmacol. 2010 Jan 15;79(2):130-6.

- Oehme I, Deubzer HE, Lodrini M, Milde T, Witt O. Targeting of HDAC8 and investigational inhibitors in neuroblastoma. Expert Opin Investig Drugs. 2009 Nov;18(11):1605-17.

- Witt O, Deubzer HE, Lodrini M, Milde T, Oehme I. Targeting histone deacetylases in neuroblastoma. Curr Pharm Des. 2009;15(4):436-47. Review.

- Witt O, Deubzer HE, Milde T, Oehme I. HDAC family: What are the cancer relevant targets? Cancer Lett. 2009 May 8;277(1):8-21. Epub 2008 Sep 27. Review.

- Milde T, Pfister S, Korshunov A, Deubzer HE, Oehme I, Ernst A, Starzinski-Powitz A, Seitz A, Lichter P, von Deimling A, Witt O. Stepwise accumulation of distinct genomic aberrations in a patient with progressively metastasizing ependymoma. Genes Chromosomes Cancer. 2009 Mar;48(3):229-38.

- Oehme I, Deubzer HE, Wegener D, Pickert D, Linke JP, Hero B, Kopp-Schneider A, Westermann F, Ulrich SM, von Deimling A, Fischer M, Witt O. Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res. 2009 Jan 1;15(1):91-9.

- Schulte JH, Kirfel J, Lim S, Schramm A, Friedrichs N, Deubzer HE, Witt O, Eggert A, Buettner R. Transcription factor AP2alpha (TFAP2a) regulates differentiation and proliferation of neuroblastoma cells. Cancer Lett. 2008 Nov 18;271(1):56-63.

- Michaelis M, Bliss J, Arnold SC, Hinsch N, Rothweiler F, Deubzer HE, Witt O, Langer K, Doerr HW, Wels WS, Cinatl J Jr. Cisplatin-resistant neuroblastoma cells express enhanced levels of epidermal growth factor receptor (EGFR) and are sensitive to treatment with EGFR-specific toxins. Clin Cancer Res. 2008 Oct 15;14(20):6531-7.

- Wegener D, Deubzer HE, Oehme I, Milde T, Hildmann C, Schwienhorst A, Witt O. HKI 46F08, a novel potent histone deacetylase inhibitor, exhibits antitumoral activity against embryonic childhood cancer cells. Anticancer Drugs. 2008 Oct;19(9):849-57.

- Wegener D, Hildmann C, Riester D, Schober A, Meyer-Almes FJ, Deubzer HE, Oehme I, Witt O, Lang S, Jaensch M, Makarov V, Lange C, Busse B, Schwienhorst A. Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorigenic assay. Biochem J. 2008 Jul 1;413(1):143-50.

- Deubzer HE, Ehemann V, Kulozik AE, Westermann F, Savelyeva L, Kopp-Schneider A, Riester D, Schwab M, Witt O. Anti-neuroblastoma activity of Helminthosporium carbonum (HC)-toxin is superior to that of other differentiating compounds in vitro. Cancer Lett. 2008 Jun 8;264(1):21-8.

- Deubzer HE, Ehemann V, Westermann F, Heinrich R, Mechtersheimer G, Kulozik AE, Schwab M, Witt O. Histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of neuroblastoma cells. Int J Cancer. 2008 Apr 15;122(8):1891-900.

- Deubzer H, Busche B, Rönndahl G, Eikel D, Michaelis M, Cinatl J, Schulze S, Nau H, Witt O. Novel valproic acid derivatives with potent differentiation-inducing activity in myeloid leukemia cells. Leuk Res. 2006 Sep;30(9):1167-75. Epub 2006 Feb 28.

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