Preclinical Research
 
Group members
Marcel Kool, PhD (Group Leader & Deputy of the Division Pediatric Neurooncology)
Hendrik Witt, MD (Physician Scientist)
Pascal Johann, MD (Physician Scientist)
Kristian Pajtler, MD (Physician Scientist)
Christin Schmidt (PhD student)
Sebastian Brabetz (PhD student)
Sander Lambo (PhD student)
 
Research interests
The main focus of the Preclinical Research Group is to translate knowledge obtained from the genomic studies into novel strategies for most optimal treatments of patients. For instance, upcoming clinical trials will select patients that have a medulloblastoma with activated SHH signaling for treatment with a SMO antagonist. Recent data from our group, however, show that many patients will not respond to this drug as can be predicted from the genomic data. These patients need to be treated with other drugs targeting the pathway more downstream. SHH signaling has our special interest as this signaling pathway seems not only be activated in medulloblastoma and therefore a target for therapy, but also in several other entities like Gliomas, ATRTs, and ETANTRs. However, for most of these other entities it is currently unclear what is activating the pathway in these tumors.
Novel drug targets, often in combination with established cytotoxic drugs and/or chemotherapy, are being investigated using model systems (cell lines and patient-derived xenografts [PDX models]). A pipeline of generating new PDX models has been set up in which we transplant every new fresh brain tumor that we get from 10 different cancer centers in Germany directly into a mouse and at the same time grow the tumor cells in vitro. Existing and newly established model systems (cell lines and PDX models) will be molecularly characterized (DNA sequencing, DNA methylation, RNA profiling) in order to have a full repertoire of model systems covering the main pediatric brain tumor entities and their respective molecular subgroups that can be used for preclinical studies. Novel compounds for treatment are being identified using high-throughput compound screenings on selected cell lines, which is done in collaboration with Joe Lewis at the EMBL. Most interesting candidate compounds are then further tested in other model systems (in vitro and in vivo). The same model systems are also being used to study mechanisms of primary and secondary drug resistance in the different tumor entities.
The genomics part of this subgroup is focused on the (epi)genomic analyses of ependymomas, ATRTs, ETANTRs and CNS-PNETs using DNA- and (mi)RNA-sequencing, DNA methylation analysis, and RNA profiling. Not much is known about what is driving these less frequent but often aggressive brain tumors. The aim is to characterize them in a better way, identify clinically relevant and distinct molecular subgroups, and find novel candidates for rational targeted therapies.
 
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Selected references:
Kool M, et al. and Lichter P, Wechsler-Reya RJ, Pfister SM. Genome sequencing of SHH medulloblastoma poredicts genotype-related response to smoothened inhibitors. Cancer Cell 2014 Mar 17;25(3):393-405.
Hovestadt V*, Jones DTW*, et al. and Radlwimmer B, Pfister SM, and Lichter P. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature2014 (in press)
Northcott PA, et al. and Lichter P, Korbel JO, Wechsler-Reya RJ, Pfister SM . Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 2014 (in press)
Mack SC*, Witt H*, et al. and Pfister SM, Taylor MD. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 2014;506:445-450.
Korshunov A, Kool M et al. Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathol 2013
Jager N, et al. and Lichter P, Pfister SM, Eils R. Hypermutation of the inactive X chromosome is a frequent event in cancer. Cell 2013;155:567-581.
Northcott PA, Jones DT,Kool M, Robinson GW, Gilbertson RJ, Cho YJ, Pomeroy SL, Korshunov A, Lichter P, Taylor MD, Pfister SM. Medulloblastoma: the end of the beginning. Nature Reviews Cancer 2012 Dec;12(12):818-34.
Korshunov A, Kool M et al. LIN28A immunoreactivity is a potent diagnostic marker of embryonal tumor with multilayered rosettes (ETMR). Acta Neuropathologica 2012 Dec;124(6):875-81.
Sturm D*, Witt H*, et al. and Jabado N, Pfister SM. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 2012 Oct 16;22(4):425-37.
Jones DT*, Jaeger N*, et al. and Eils R, Pfister SM, Lichter P. Dissecting the genomic complexity underlying medulloblastoma. Nature.2012 Aug 2;488(7409):100-5.
Northcott PA, et al. and Taylor MD. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 2012 Aug 2;488(7409):49-56.
Witt H*, Mack SC*, et al. and Taylor MD, Pfister SM. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 2011 Aug 16;20(2):143-57.