Dr. Marc Zuckermann
Group leader "Preclinical modeling"
Hopp Children's Cancer Center Heidelberg
Im Neuenheimer Feld 580
Our Group “Preclinical Modeling” headed by Dr. Marc Zuckermann, is part of Prof. Stefan Pfister’s division of “Pediatric Neurooncology” and focusses on establishing and utilizing in vivo brain tumor models for preclinical research.
We are using somatic gene delivery, most often in utero electroporation, to induce selected genetic aberrations orthotopically. Thereby, we are able to rapidly validate different combinations of candidate hits that have been identified in patient samples. Tumors derived from this approach are allografted, providing allogeneic and immunocompetent models that are crucial for subsequent studies.
The established allografts and PDX models of collaborating groups are utilized to investigate biological questions and to conduct preclinical experiments with modern treatment approaches. These include elaborate drug combinations, but also experimental therapies using adeno-associated virus. In addition, we aim to perform CRISPR-based in vivo screens in the future.
Besides analyzing the efficacy of new and promising inhibitors in vivo, we are also investigating an experimental therapy approach. Within this project, we are combining selected AAV variants with oncogene-specific CRISPR-nucleases to treat orthotropic xeno- and allografts under various conditions. In case we will observe a response to the treatment, the system will be refined and extended to multiple other tumor entities.
In clinical trials, single agent modalities against various targets have displayed potent initial response, yet acquired resistance and tumor relapse is often inevitable. This holds true for many preclinical studies, also when using promising, modern inhibitors. Thus, we are currently aiming at generating resistant tumors in vivo in order to analyze the underlying resistance mechanisms. These efforts will not only provide valuable insight into tumor evolution under treatment but, most importantly, also inform future combinatorial therapy approaches.
1. Zuckermann, M., V. Hovestadt, C. B. Knobbe-Thomsen, M. Zapatka, P. A. Northcott, K. Schramm, J. Belic, D. T. Jones, B. Tschida, B. Moriarity, D. Largaespada, M. F. Roussel, A. Korshunov, G. Reifenberger, S. M. Pfister, P. Lichter, D. Kawauchi, and J. Gronych. 'Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling', Nature Communications, 6: 7391.
2. Zuckermann, M., D. Kawauchi, and J. Gronych. 'Applications of the CRISPR/Cas9 system in murine cancer modeling', Brief Funct Genomics, 16: 25-33.
3. Zuckermann, M., M. Hlevnjak, H. Yazdanparast, M. Zapatka, D. T. W. Jones, P. Lichter, and J. Gronych. 'A novel cloning strategy for one-step assembly of multiplex CRISPR vectors', Scientific Reports, 8: 17499.