National Center of Competence in Research - NCCR Molecular Oncology

Dr. sc. nat. Monika E. Hegi

Dr. Monika Hegi completed her studies at the Federal Institute of Technology in Zurich with a Doctorate in Natural Sciences in 1989, and pursued post-doctoral training in molecular toxicology and molecular carcinogenesis at the National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, NC, USA (1989-1993). Since 1993 her research is focused on brain tumors (Institute of Neuropathology, University Hospital Zurich). In 1998 she was appointed head of the Laboratory of Tumor Biology and Genetics in the Department of Neurosurgery at the CHUV in Lausanne. She obtained the title of Private Docent (PD) and “Maître d’Enseignement et de Recherche” (MER) in 2005 and was appointed Associate Professor for Experimental and Translational Neuro-Oncology in 2009. Her work on translational cancer research was acknowledged with the 2002 Award of the Jacqueline Seroussi Memorial Foundation for Cancer Research (Israel), and the Wenner Prize 2006 for Cancer Research (Swiss).
Monika Hegi chairs translational research in the Brain Tumor Group of the European Organization for Research and Treatment of Cancer (EORTC) and is project leader in the program of the NCCR Molecular Oncology since 2001.

Laboratory of Tumor Biology and Genetics
Centre Universitaire Romand de Neurochirurgie
Centre Hospitalier Universitaire Vaudois (CHUV)

Gene expression signatures in human glioblastoma and their implications for tumor biology and treatment of cancer

Glioblastoma most malignant brain tumor

Glioblastoma is the most malignant and most common type of primary brain tumors in adults with a yearly incidence of 5-7 persons per 100.000. This is a rapidly growing tumor and despite modern therapy usually has a fatal outcome with a median life expectancy of 13-17 months after diagnosis. Thus new avenues have to be taken to find effective treatment modalities, requiring more insights into aberrant regulatory molecular mechanisms relevant for tumor biology and treatment.

Molecular profiles and biological behavior

We have established molecular profiles of glioblastoma, obtained from patients enrolled in a randomized clinical trial, comprising information on global gene expression, and some epigenetic and genome-wide genetic alterations. The goal was to subclassify tumors in a biologically meaningful manner, providing insights into molecular mechanisms relevant for treatment. This study demonstrated that the presence of an epigenetically inactivated MGMT gene in the tumor of the patients, coding for a DNA-repair enzyme, conferred benefit from alkylating agent chemotherapy. At present, the MGMT methylation status is the strongest prognostic factor for outcome of newly diagnosed glioblastoma patients and a powerful predictor of response to alkylating chemotherapy. The MGMT-status is now widely used for patient stratification and patient selection in clinical trials for brain tumor patients. Hence providing evidence that molecular tumor profiles will lead to rational, individualized treatment decisions and incite further research to discover new drugable targets.

Molecular signature of “Tumor Stem-Like Cells”

The recent identification of “stem like cells” in several tumor types, including glioma, has led to new concepts in cancer research. It has been hypothesized that tumor stem-like cells represent the source of tumor cell renewal. This implies that a minority population of cancer stem-like cells comprised in a tumor may determine the biological behavior thereof, including proliferation, progression, and subsequently response to therapy. We isolate cancer stem-like cells from glioblastoma, characterize their properties and analyze their molecular profiles including genetic and epigenetic information to gain insights into underlying molecular mechanisms driving the biological behavior. Respective molecular signatures of “Stemness” will subsequently be sought in expression profiles of glioblastoma that may allow us to establish an association with the biological and clinical behavior of the tumor. Such insights into the molecular biology of tumor stem-like cells are required to eventually target this tumor cell compartment.

List of publications

Murat, A., Migliavacca, E., Hussain, S.F., Heimberger, A.B., Desbaillets, I., Hamou, M.F., Ruegg, C., Stupp, R., Delorenzi, M., and Hegi, M.E. Modulation of angiogenic and inflammatory response in glioblastoma by hypoxia. PLoS ONE 4, e5947 (2009)

Shay, T., Lambiv, W.L., Reiner-Benaim, A., Hegi, M.E., and Domany, E. Combining chromosomal arm status and significantly aberrant genomic locations reveals new cancer subtypes. Cancer Inform 7, 91-104 (2009)

Shnaper, S., Desbaillets, I., Brown, D.A., Murat, A., Migliavacca, E., Schluep, M., Ostermann, S., Hamou, M.F., Stupp, R., Breit, S.N., et al. Elevated levels of MIC-1/ GDF15 in the cerebro-spinal fluid (CSF) of patients are associated with glioblastoma and worse outcome. Int J Cancer 125, 2624-2630 (2009)

Sivasankaran, B., Degen, M., Ghaffari, A., Hegi, M.E., Hamou, M.-F., Ionescu, M.-C.S., Zweifel, C., Tolnay, M., Wasner, M., Mergenthaler, S., et al. Tenascin-C Is a Novel RBPJ{kappa}-Induced Target Gene for Notch Signaling in Gliomas. Cancer Res 69, 458-465 (2009)

Stupp, R., Hegi, M.E., Mason, W.P., van den Bent, M.J., Taphoorn, M.J., Janzer, R.C., Ludwin, S.K., Allgeier, A., Fisher, B., Belanger, K., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10, 459-466 (2009)

Lange, K., Kammerer, M., Saupe, F., Hegi, M.E., Grotegut, S., Fluri, E., and Orend, G. Combined lysophosphatidic acid/platelet-derived growth factor signaling triggers glioma cell migration in a tenascin-C microenvironment. Cancer Res 68, 6942-6952 (2008)

Vlassenbroeck, I., Califice, S., Diserens, A.C., Migliavacca, E., Straub, J., Di Stefano, I., Moreau, F., Hamou, M.F., Renard, I., Delorenzi, M., et al. Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma. J Mol Diagn 10, 332-337 (2008)

Hegi, M.E., Liu, L., Herman, J.G., Stupp, R., Wick, W., Weller, M., Mehta, M.P., and Gilbert, M.R.. Correlation of MGMT Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity. J Clin Oncol. (2008)

Gorlia, T., van den Bent, M.J., Hegi, M.E., Mirimanoff, R.-O., Eisenhauer, E., Belanger, K., Brandes, A.A., Allgeier, A., Lacombe, D., and Stupp, R. Nomogrgrams for predicting survival of patiens with newly diagnosed glioblastoma multiforme. A prognostic factor analysis of EORTC/NCIC trial 26981-22981/CE.3. Lancet Oncol. 9, 29-38 (2008)

Brandes, A.A., Franceschi, E., Tosoni, A., Hegi, M.E., and Stupp, R. Epidermal Growth Factor Receptor Inhibitors in Neuro-oncology: Hopes and Disappointments. Clin Cancer Res. 14(4):957-60 (2008)

Preusser, M., Heinzl, H., Gelpi, E., Schonegger, K., Haberler, C., Birner, P., Marosi, C., Hegi, M., Gorlia, T., and Hainfellner, J.A. Histopathologic assessment of hot-spot microvessel density and vascular patterns in glioblastoma: Poor observer agreement limits clinical utility as prognostic factors: a translational research project of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Cancer. 107(1):162-70 (2006)

Stupp, R., van den Bent, M.J., and Hegi, M.E. Optimal role of temozolomide in the treatment of malignant gliomas. Curr Neurol Neurosci Rep 5, 198-206 (2005)

Hegi, M.E., Diserens, A.C., Gorlia, T., Hamou, M.F., de Tribolet, N., Weller, M., Kros, J.M., Hainfellner, J.A., Mason, W., Mariani, L., Bromberg, J.E., Hau, P., Mirimanoff, R.O., Cairncross, J.G., Janzer, R.C., Stupp, R. MGMT gene silencing and benefit from temozolomide in glioblastoma. New England Journal of Medecine 352, 997-1003 (2005)

Ruiz, C., Huang, W., Hegi, M.E., Lange, K., Hamou, M.F., Fluri, E., Oakeley, E.J., Chiquet-Ehrismann, R., Orend, G. Differential Gene Expression Analysis Reveals Activation of Growth Promoting Signaling Pathways by Tenascin-C. Cancer Research 64, 7377-7385 (2004)

Hegi, M.E., Diserens, A.C., Godard, S., Dietrich, P.Y., Regli, L., Ostermann, S., Otten, P., Van Melle, G., de Tribolet, N., Stupp, R. Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide. Clinical Cancer Research 10, 1871-1874 (2004)

Lachat, Y., Diserens, A.C., Nozaki, M., Kobayashi, H., Hamou, M.F., Godard, S., De Tribolet, N., Hegi, M.E. INK4a/Arf is required for suppression of EGFR/DeltaEGFR(2-7).-dependent ERK activation in mouse astrocytes and glioma. Oncogene 23, 6854-63 (2004)

Godard, S., Getz, G., Delorenzi, M., Farmer, P., Kobayashi, H., Desbaillets, I., Nozaki, M., Diserens, A.-C., Hamou, M.-F., Dietrich, P. Y., Regli, L., Janzer, R.C., Stupp, R., Bucher, P., de Tribolet, N., Domany, E., Hegi, M. E. Classification of human astrocytic gliomas on the basis of gene expression, A correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. Cancer Research 63, 6613-6625 (2003)

Reviews

Hegi, M.E., Sciuscio, D., Murat, A., Levivier, M., and Stupp, R. Epigenetic deregulation of DNA repair and its potential for therapy. Clin Cancer Res 15, 5026-5031 (2009)

Stupp, R., Hegi, M.E. Methylguanine methyltransferase testing in glioblastoma: when and how? J Clin Oncol. 25(12):1459-60 (2007)

Hau, P., Stupp, R., and Hegi, M.E. MGMT methylation status: The advent of stratified therapy in glioblastoma? Disease Markers 22, 1-8 (2007)

Stupp, R., Hegi, M.E. Targeting brain-tumor stem cells. Nat Biotechnol. 25(2):193-4 (2007)

Stupp, R., and Hegi, M.E. Neuro-oncology: oligodendroglioma and molecular markers. Lancet Neurol 6, 10-12 (2007)

Hegi, M.E. and Stupp, R. Correlative Studies in Neuro-Oncology Trials: Should they influence treatment. Curr Oncol Rep, 8(1):54-7 (2006)

Hegi, M.E., Murat, A., Lambiv, W.L., and Stupp, R. Brain tumors: molecular biology and targeted therapies. Ann Oncol 17 Suppl 10, x191-x197 (2006)

Stupp, R., Hegi, M.E., van den Bent, M.J., Mason, W.P., Weller, M., Mirimanoff, R.O., and Cairncross, J.G. Changing paradigms - an update on the multidisciplinary management of malignant glioma. Oncologist 11, 165-180 (2006)

van den Bent, M.J., Hegi, M.E., and Stupp, R. Recent developments in the use of chemotherapy in brain tumours. Eur J Cancer 42(5):582-8 (2006)

Dehdashti, A.R., Hegi, M.E., Regli, L., Pica, A., and Stupp, R. New trends in the medical management of glioblastoma multiforme: the role of temozolomide chemotherapy. Neurosurg Focus 20(4):E6 (2006)

Stupp, R., van den Bent, M.J., Hegi, M.E. Optimal role of temozolomide in the treatment of malignant gliomas. Current Neurology and Neuroscience Reports, 5,198-206 (2005)

Scientific articles in anthologies

Stupp, R., Hegi, M. E. Recent developments in the management of malignant glioma. In, ASCO 2003 Educational Book. Perry, M. C. (Ed). 779-788, American Society of Clinical Oncology. Alexandria, VA, (2003)