DKFZ Junior Group Brain Tumor Translational Targets

Dr. Violaine Goidts

Targeting GSCs to achieve complete degeneration of glioblastoma; a) Currently, the resistance of GSCs to radio- and chemotherapy allows this rare subpopulation of cells to persist after GBM treatment. Patients relapse with an aggressive tumour enriched in GSCs. b) Targeting GSCs with additional therapeutics will deplete this resistant sub-population, allowing complete degeneration of the tumour.
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Due to its location, aggressiveness and diffuse growth pattern, glioblastoma therapy is tremendously challenging and no significant improvement in survival has been achieved over the past decade. The annual incidence of this highly aggressive brain tumor varies from 5 to 7 per 100,000, with around 25,000 new cases being diagnosed in the European Union each year. There is an urgent need for advances in glioblastoma therapy, which presents many opportunities for translational research. In recent years, much evidence has been gathered to reveal a small sub-population of cancer cells that are capable of continuous self-renewal and can regenerate the tumor, which are known as glioblastoma stem-like cells (GSCs). These cells have been suggested to be responsible for the current therapy resistance of glioblastoma. In this respect, considerable effort must be directed towards the targeting of GSCs, which should cause the tumor to lose its ability to generate new cells, ultimately leading to complete tumor degeneration.

Recently, the advent of high-throughput next-generation sequencing technologies has led to a new era in the study of de novo mutations, helping to uncover disease precondition and mechanism. However, these informative analyses do not account for post-translational modifications that lead to oncogene activation or tumor suppressor gene inhibition. High-throughput loss-of-function phenotypic screens, which form the basis of the strategy of our group have proven to resolve this issue, identifying new druggable therapeutic targets for glioblastoma which may otherwise be overlooked. In addition our use of a fungal extract library in an unbiased drug screening approach has allowed for the identification of compounds which impair viability of GSCs in a cancer-specific manner. We focus our research on the discovery of important key players in the maintenance of stemness and viability of GSCs as well as of mechanisms of therapy resistance. Ultimately, we aim to translate our findings and perform preclinical studies to assess the therapeutic efficiency of novel drug candidates and of inhibiting newly identified targets for brain tumor patients.

Contact

Dr. Violaine Goidts
Brain Tumor Translational Targets (B067)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 580
69120 Heidelberg
Tel: +49 6221 42-4635

Selected Publications

  • Goidts V., Bageritz J., Puccio L., Nakata S., Zapatka M., Barbus S., Toedt G., Campos B., Momma S., Herold-Mende C., Lichter P., Radlwimmer B. (2012) RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival. Oncogene, 31: 3235-43
  • Bageritz J., Puccio L., Piro R.M., Hovestadt V., Phillips E., Pankert T., Lohr J., Herold-Mende C., Lichter P., Goidts V.(2014) Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1. Cell Death Differ., 21(6):929-40
  • Cheng P., Phillips E., Kim S.-H., Taylor D., Hielscher T., Puccio L., Hjelmeland A., Lichter P., Nakano I., Goidts V. (2015) Kinome-wide shRNA Screen Identifies the Receptor Tyrosine Kinase AXL as a Key Regulator for Mesenchymal Glioblastoma Stem-Like Cells. Stem Cell Rep., 4(5):899-913
  • Kim S.H., Ezhilarasan R., Phillips E., Gallego-Perez D., Sparks A., Taylor D., Ladner K., Furuta K., Sabit H., Chhipa R., Cho J.H., Beck S., Kurozumi K., Kuroiwa T., Iwata R., Asai A., Kim J., Sulman E.P., Cheng S., Lee L.J., Nakada M., Guttridge D., DasGupta B., Goidts V., Bhat K.P., Nakano I. (2016) Serine/Threonine kinase MLK4 determines Mesenchymal Identity in Glioma Stem Cells in an NF-?B-dependent manner. Cancer Cell,
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