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
- 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.
- 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.
- 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.
- 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.
