Principal Investigator

Prof. Dr. Alexander Schramm

Molecular Oncology Group
University Hospital Essen

Prof. Dr. Alexander Schramm

Summary

Neuroblastoma is the most common extracranial tumor of childhood. Treatment modalities for neuroblastoma include external-beam radiation to local sites. However, the molecular factors that determine the sensitivity and resistance of neuroblastoma to IR remain elusive. Favorable neuroblastomas are characterized by genomic stability and high expression of the TrkA neurotrophin receptor. In contrast, unfavorable neuroblastomas are characterized by genomic instability and expression of the TrkB neurotrophin receptor. In vitro, we have identified TrkA as a master regulator of differentiation programs, governing global mRNA as well as miRNA expression (Schramm et al., 2012). In the second phase of the project, we will focus on the analyses of TrkA and TrkB effector genes on checkpoint activation, DNA repair, and cell death in irradiated neuroblastoma cells. Moreover, we aim to define the molecules and pathways that link neurotrophin receptors, DNA repair, and cell survival. Understanding the mechanisms of radioresistance in neuroblastoma is expected to reveal novel therapeutic targets for radiosensitization.

Henssen A, Althoff K, Odersky A, Beckers A, Koche R, Speleman F, Schäfers S, Bell E, Nortmeyer M, Westermann F, De Preter K, Florin A, Heukamp L, Spruessel A, Astrahanseff K, Lindner S, Sadowski N, Schramm A, Astorgues-Xerri L, Riveiro ME, Eggert A, Cvitkovic E, Schulte JH. Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition. Clin Cancer Res. 2016 22(10):2470-81

Peifer M, Hertwig F, Roels F, Dreidax D, Gartlgruber M, Menon R, Krämer A, Roncaioli JL, Sand F, Heuckmann JM, Ikram F, Schmidt R, Ackermann S, Engesser A, Kahlert Y, Vogel W, Altmüller J, Nürnberg P, Thierry-Mieg J, Thierry-Mieg D, Mariappan A, Heynck S, Mariotti E, Henrich KO, Gloeckner C, Bosco G, Leuschner I, Schweiger MR, Savelyeva L, Watkins SC, Shao C, Bell E, Höfer T, Achter V, Lang U, Theissen J, Volland R, Saadati M, Eggert A, de Wilde B, Berthold F, Peng Z, Zhao C, Shi L, Ortmann M, Büttner R, Perner S, Hero B, Schramm A, Schulte JH, Herrmann C, O'Sullivan RJ, Westermann F, Thomas RK, Fischer M. (2015) Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature. 526(7575):700-4

Schramm A, Köster J, Assenov Y, Althoff K, Peifer M, Mahlow E, Odersky A, Beisser D, Ernst C, Henssen AG, Stephan H, Schröder C, Heukamp L, Engesser A, Kahlert Y, Theissen J, Hero B, Roels F, Altmüller J, Nürnberg P, Astrahantseff K, Gloeckner C, De Preter K, Plass C, Lee S, Lode HN, Henrich KO, Gartlgruber M, Speleman F, Schmezer P, Westermann F, Rahmann S, Fischer M, Eggert A, Schulte JH. (2015) Mutational dynamics between primary and relapse neuroblastomas. Nat Genet. 47(8):872-7.

Schwermer M, Lee S, Köster J, van Maerken T, Stephan H, Eggert A, Morik K, Schulte JH, Schramm A. (2015) Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors. Oncotarget. 6(17):15425-35.

Althoff K, Beckers A, Bell E, Nortmeyer M, Thor T, Sprüssel A, Lindner S, De Preter K, Florin A, Heukamp LC, Klein-Hitpass L, Astrahantseff K, Kumps C, Speleman F, Eggert A, Westermann F, Schramm A, Schulte JH. (2014) A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies. Oncogene; doi:10.1038/onc.2014.269.

Pajtler KW, Mahlow E, Odersky A, Lindner S, Stephan H, Bendix I, Eggert A, Schramm A*, Schulte JH*. (2014; *= equal contribution) Neuroblastoma in dialog with its stroma: NTRK1 is a regulator of cellular cross-talk with Schwann cells. Oncotarget 5(22),11180–11192.