gms | German Medical Science

62nd Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Polish Society of Neurosurgeons (PNCH)

German Society of Neurosurgery (DGNC)

7 - 11 May 2011, Hamburg

Targeting the prognostic marker ALDH1 overcomes temozolomide resistance in human glioblastoma patients with unfavourable MGMT status

Meeting Abstract

  • F. Ringel - Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München
  • A. Schäfer - Sektion für Neuropathologie des Instituts für Pathologie, Klinikum rechts der Isar, Technische Universität München, München
  • J. Teufel - Sektion für Neuropathologie des Instituts für Pathologie, Klinikum rechts der Isar, Technische Universität München, München
  • J. Gempt - Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München
  • Y.M. Ryang - Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München
  • H. Pape - Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München
  • B. Meyer - Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München
  • J. Schlegel - Sektion für Neuropathologie des Instituts für Pathologie, Klinikum rechts der Isar, Technische Universität München, München

Deutsche Gesellschaft für Neurochirurgie. Polnische Gesellschaft für Neurochirurgen. 62. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgen (PNCH). Hamburg, 07.-11.05.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. DocMI.05.09

DOI: 10.3205/11dgnc218, URN: urn:nbn:de:0183-11dgnc2180

Published: April 28, 2011

© 2011 Ringel et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Outline

Text

Objective: The prognosis of patients with glioblastoma (GBM) remains poor despite aggressive therapeutic regimens, including radical surgical resection, radiation and chemotherapy. Adjuvant chemotherapy with temozolomide (TMZ) significantly increased the overall survival but predominantely when the MGMT promoter is epigenetically silenced (MGMT-). To date, no comparable therapeutic approach is available for GBM patients with an unfavourable MGMT expression status (MGMT+). Tumor re-growth in MGMT+ and MGMT- GBM corroborates the tumor stem cell (TSC) paradigm, postulating that a therapy-resistant subpopulation of cells harbors the ability to keep the tumor alive and growing. Recently, we presented aldehyde dehydrogenase 1 (ALDH1) as a marker for glioblastoma cells with stem cell capacity.

Methods: To further elucidate the role of ALDH1, glioblastoma specimens were immunhistochemically analyzed for ALDH1 expression and correlated to clinical outcome. Furthermore, established and primary glioblastoma cell lines were exposed to TMZ in the presence and absence of ALDH inhibitors.

Results: Immunohistochemical analysis of ALDH1 expression in glioblastoma specimens revealed a significant correlation between high ALDH1 levels and poor survival. Moreover, the combination of MGMT promoter status and ALDH1 expression resulted in a more precise estimation of prognosis than MGMT status alone. ALDH1 overexpression correlates with the resistance to TMZ in established and primary MGMT+ GBM cell lines, while concomitant inhibition of ALDH1 by 4-diethylaminobenzaldehyde (DEAB) or tetraethylthiuramdisulfide (DSF) re-sensitized the cells significantly. Application of TMZ in combination with DEAB strikingly attenuated the stem cell capacity of both MGMT+ and MGMT- cells.

Conclusions: These findings demonstrate that ALDH1 is a marker for brain tumor stem cell capacities and a strong predictor of clinical outcome. Therefore, ALDH1 is a potential target for an improved therapy of MGMT positive GBM.