Clinical Cooperation Unit Pediatric Oncology

Prof. Dr. med. Olaf Witt

HDAC-inhibitors induce differentiation in neuroblastoma cells
© dkfz.de

The goal of the Pediatric Oncology Clinical Cooperation Unit (CCU) is to advance cure rates and reduce toxicity for children and adolescents with tumors of the nervous system. This is achieved through translating basic science discoveries in genetics, epigenetics and molecular mechanisms of tumorigenesis and therapy resistance into molecularly informed clinical trials. Epigenetic programs are reversibly controlled by an array of enzymes, including the family of histone deacetylases (HDACs). Understanding the molecular biology and selective targeting of individual HDACs comprises one of the major interests of the Pediatric Oncology CCU. Our research groups, headed by Ina Oehme and Till Milde, have identified particular HDAC family members 2, 8, 10 and 11 controlling differentiation, cell survival mechanisms, developmental pathways and self-renewal in neuroblastoma and brain tumors. As a consequence, we are developing small molecule compounds that specifically inhibit distinct HDACs for therapeutic purposes. We are translating our experimental findings into clinical practice through the development of individual targeted treatment protocols for children and adolescents with relapsed cancers, as well as by conducting Phase I-III clinical trials in pediatric oncology that are based on rational molecular concepts. To this end, we have initiated a first nationwide registry trial for personalized oncology in pediatrics (INFORM) based on a clinical sequencing platform together with cooperating partners from DKFZ, DKTK and NCT. In order to speed up the translational process, we have opened the first Center for Individualized Pediatric Oncology (ZIPO) funded by the NCT 3.0 program in collaboration with the Department of Pediatric Oncology, University Hospital of Heidelberg.

FUTURE OUTLOOK

  1. Drug target validation: We will define the tumor biological function of individual HDACs with respect to regulation of the human acetylome and downstream pathways in pediatric cancers of the nervous system. To this end, we will include primary tumor material, cancer stem cell and animal models in our projects. This will facilitate the identification of potential biomarkers for treatment response prediction and establish the basis for patient selection in future trials involving selective HDAC inhibitors.
  2. Drug development: We will pursue the development of selective small molecule HDAC inhibitors for Phase I clinical trials. In addition, we aim to identify synthetic lethal interacting pathways disrupting multiprotein repressor complexes involving HDACs in order to facilitate rational combination therapies in the future.
  3. Disease models: We will extend our primary tumor model bank for pediatric neuronal cancers including LGG, and develop novel genetic models based on primary normal and tumor material. In addition, we are exploring new culture techniques in order to improve the predictive value of preclinical models for clinical therapy response.
  4. Clinical trials: We will continue to expand our early Phase I and II clinical trial program in pediatric oncology at the NCT, focusing on personalized, molecular informed studies (INFORM) as well as conducting international Phase III trials for low grade gliomas in children. We will set of a co-clinical trial program aiming for integrative functional analysis of primary tumor cell response for online clinical decision making.

Contact

Prof. Dr. med. Olaf Witt
Pediatric Oncology (G340)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 42 3570

Selected Publications

  • Worst BC, van Tilburg CM, Balasubramanian GP, Fiesel P, Witt R, Freitag A, Boudalil M, Previti C, Wolf S, Schmidt S, Chotewutmontri S, Bewerunge-Hudler M, Schick M, Schlesner M, Hutter B, Taylor L, Borst T, Sutter C, Bartram CR, Milde T, Pfaff E, Kulozik AE, von Stackelberg A, Meisel R, Borkhardt A, Reinhardt D, Klusmann JH, Fleischhack G, Tippelt S, Dirksen U, Jürgens H, Kramm CM, von Bueren AO, Westermann F34, Fischer M35, Burkhardt B36, Wößmann W37, Nathrath M38, Bielack SS39, Frühwald MC, Fulda S, Klingebiel T, Koscielniak E, Schwab M, Tremmel R, Driever PH, Schulte JH, Brors B, von Deimling A, Lichter P, Eggert A, Capper D, Pfister SM, Jones DT, Witt O. Next-generation personalised medicine for high-risk paediatric cancer patients - The INFORM pilot study. Eur J Cancer. 2016 Sep;65:91-101. doi: 10.1016/j.ejca.2016.06.009. Epub 2016 Jul 29.
  • Oehme I, Linke JP, Böck BC, Milde T, Lodrini M, Hartenstein B, Wiegand I, Eckert C, Roth W, Kool M, Kaden S, Gröne HJ, Schulte JH, Lindner S, Hamacher-Brady A, Brady NR, Deubzer HE, Witt O. Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc Natl Acad Sci USA. 2013 Jul 9;110(28):E2592-601. doi: 10.1073/pnas.1300113110. Epub 2013 Jun 25.
  • Selt F, Hohloch J, Hielscher T, Sahm F, Capper D, Korshunov A, Usta D, Brabetz S, Ridinger J, Ecker J, Oehme I, Gronych J, Marquardt V, Pauck D, Ba?chli H, Stiles CD, von Deimling A, Remke M, Schuhmann MU, Pfister SM, Brummer T, Jones DT, Witt O, Milde T. Establishment and application of a novel patient-derived KIAA1549:BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing. Oncotarget (in press)
  • Ecker J, Oehme I, Mazitschek R, Korshunov A, Kool M, Hielscher T, Kiss J, Selt F, Konrad C, Lodrini M, Deubzer HE, von Deimling A, Kulozik AE, Pfister SM, Witt O, Milde T. Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma. Acta Neuropathol Commun. 2015 Apr 3;3:22. doi: 10.1186/s40478-015-0201-7.
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