People and Projects

Dr. Marta Cook, University Hospital Heidelberg, Department of Pediatric Oncology

CV

High-grade glioma evolution under targeted therapy

Tumors of the central nervous system are the leading cause of cancer-related deaths in children with high-grade glioma (HGG) being one of the most lethal forms. Gen fusions of the RTKs ALK, NTRK and MET have been identified as tumorigenic alterations in pediatric glioma. Based on these findings, we recently established multiple mouse models, driven by the respective fusion genes. The aim of this project is to monitor the evolution of different HGGs under targeted inhibitor treatment and to evaluate rationally derived therapy approaches including alternative treatment protocols with higher drug dose and prolonged treatment. In general, the analysis of cell populations on single cell level under inhibitor treatment will provide valuable insights into in vivo tumor cell adaption in response to therapy. This knowledge of inhibitor-specific treatment-related tumor cells adoption, will inform combinatorial therapy approaches, which we will directly evaluate in vitro. The project therefore provides an immense potential to discover novel combinatorial therapy approaches and to inform future clinical trials.

Dr. med. Tanja Eichkorn, University Hospital Heidelberg, Department of Radiation Oncology

Effects and side effects on healthy tissue due to proton radiotherapy in patients with IDH-mutated low grade glioma

Especially in patients with a comparatively good prognosis the avoidance of late sequelae is of utmost importance. Owing to the advantageous physical properties of protons with an inverse depth dose profile compared to photons, there is a strong rationale for the use of protons in low-grade glioma. On one hand there is increasing evidence for improved neurocognitive outcome but on the other hand the incidence of clinically relevant radiation-induced brain injuries might be higher due to underestimation of the radiobiological effectiveness (RBE) of protons. The main goal of the project is to gain a quantitative estimate on the RBE and to develop an interdisciplinary biological model and strategies for proton beam radiotherapy planning. The prospective evaluation of these models will be a very important step towards individualized and side effect-reducing radiation oncology.

Rajiv Kumar Khajuria, University Medical Centre Mannheim, Department of Neurosurgery

CV

Dynamic Multimodal Genome-Scale Profiling of the Response to Current Treatment Strategies in Human Glioblastoma

While considerable insight into glioblastoma (GB) pathomechanisms has been gained at the epigenetic, transcriptional and single signaling pathway levels, the repertoire of molecular regulators of underlying disease mechanisms remains to be fully defined and functionally characterized. The key role of post-transcriptional regulation in the maintenance of different cell types including cancer cells is increasingly appreciated. The importance of such regulation is emphasized by the observation that only a fraction of the variation in cellular protein levels can be explained through transcriptional changes. However, systematic approaches to define and characterize regulators of such post-transcriptional processes and functional consequences of perturbations of these remain largely unexplored, particularly in GBs. In this project, we set out to define the post-transcriptional landscape in human glioblastoma and explore how alterations in this in response to currently clinically relevant therapies may facilitate treatment resistance and thus, may guide the development of novel molecularly-informed treatment strategies.

Yingying Liang, MD, University Hospital Heidelberg, Department of Neurology

CV

Epigenetic vulnerabilities in IDH mutant gliomas

Lower grade gliomas harbor isocitrate dehydrogenase (IDH) mutations and subsequent epigenetic changes e.g. histone modifications as well as DNA hypermethylation that leads to the CpG island promoter methylator phenotype (CIMP). The epigenetic remodeling of gliomas engenders the therapeutic targeting potential. DNA methyltransferase inhibitors (DNMTi) have been utilized in the clinical management of hematological malignancies. Previously, we have shown the utility of a DNMT1 inhibitor decitabine in reducing the tumorigenic potential of IDH mutant gliomas and identified DNMT expression levels and TERT promoter mutation status as potential determinants of response to decitabine. Here, we aim to investigate additional crucial determinants for the therapeutic potential of DNMTi and determine whether DNMTi may play a role in anti-tumor immune signaling in gliomas.

Our goal is to elucidate whether DNMTi can be combined with immune therapies such as checkpoint inhibitors in preclinical models. Specifically, as has been shown for other solid tumors, we seek to determine whether and which immune activation occurs during epigenetic therapy in gliomas and hope that epigenetic therapy will emerge as a minimally toxic and efficacious treatment option for patients with brain tumor.

Dr. med. Irada Pflüger, University Hospital Heidelberg, Department of Neuroradiology

CV

Automated image analysis of MRI data of brain tumors using artificial neural networks (ANN)

The current method for the precise assessment of the efficiency of a new therapy for brain tumors is mainly based on manual measurements of the targeted lesions according to the Response Assessment in Neuro-Oncology criteria, which may potentially be less accurate and reproducible than volumetric measurements. However, this method is not widely used in clinical routine due to the complex and time-consuming post-processing of MRI data. Building on our preliminary work the purpose of this project is a development and a validation of a deep-learning driven image-processing pipeline, that allows fully automated processing of MRI-data in neurooncology imaging and augment its integration in the clinical workflow, to provide precise quantitative metrics of tumor, for the management of patients with brain tumors and to accelerate clinical trials of targeted therapies. In summary, I am confident that our project and tools offer a comprehensive set of solutions that span the multifaceted healthcare problems in brain tumor patients.

Dr. med. Annekathrin Reinhardt, University Hospital Heidelberg, Department of Neuropathology

CV

Development of a mass spectrometry assay to assess the activity of oncogenic signal transduction pathways in glioblastoma

For patients diagnosed with glioblastoma of unmethylated MGMT promoter alternatives to conventional temozolomide chemotherapy are increasingly considered. Highly efficient inhibitors targeting a broad range of signal transduction pathways have already been developed and some of these are also applied in the clinic. The basis of finding a suitable target for the treatment of a tumor is knowledge about its signal transduction pathway activity. However, the precise quantification of signal transduction components and particularly their posttranslational modifications providing essential information about their activation status is challenging. A frequent mechanism of posttranslational modification and pathway activation is protein phosphorylation. With this project we set out to establish a targeted assay for the analysis of defined phosphoproteins in tumor tissue. This assay may provide promising support of clinical studies focusing on the treatment of patients with MGMT unmethylated glioblastomas and may pave the way to targeted approaches based on specific inhibitors.

Dr. med. Philipp Sievers, University Hosptial Heidelberg, Department of Neuropathology

CV

Dissecting molecular progression and intra-tumoral heterogeneity of meningioma on the single-cell level

Meningiomas are the most frequent primary CNS tumors. Although the majority of meningioma patients can be cured by resection alone, about 20% of tumors recur and require additional treatment. Among these recurrent meningiomas, a large fraction constitutes cases that were initially inconspicuous in neuropathological work-up, but transform into more aggressive tumors upon recurrence. The identification of meningiomas with potential for malignant progression is challenging on basis of current diagnostic approaches.

Molecular markers hold great potential to assist in more reliable risk prediction for meningioma patients. There is already a well-established molecular concept of progression in meningiomas based on the accumulation of (epi-)genetic alterations. However, the evolution of aggressive subclones in otherwise low-grade meningiomas is unknown.

Investigating the development of molecular alterations in progressive meningioma on cellular fractions and specific compartments, and correlate these findings with histology will lead to identification of the decisive steps in malignant transformation of meningioma, which in turn present potential targets. In parallel, the correlation with morphology will highlight histological patterns that should alert about the malignant potential of a seemingly benign meningioma.

Dr. med. Robin Wagener, University Hosptial Heidelberg, Department of Neurology

CV

Anatomical and transcriptional investigation of different types of cancer stem cells in primary and recurrent glioblastoma

In normal brain development neurogenesis is based upon cellular hierarchies: stem cells with self-renewing capacities give birth to different types of transient amplifying cells, which in turn create lineage-restricted cells, in a temporally restricted order. Several studies could demonstrate that emergence of primary brain tumors (including glioblastoma) are built upon cellular hierarchies as well: the tumor contains self-renewing, cancer stem cells (CSCs), which create cell populations that resemble transient amplifying cells, which create tumor cells. Additionally, CSCs seem to have an exceptional resistance to chemotherapy and radiotherapy, making them key players in disease progression and recurrence of GB. In this project we want to investigate CSCs and get a better understanding of their biology. We aim to better understand their variety, their spatial positioning within the tumor and their microenvironment, as well as their (different?) transcriptional programs in different states of the disease and after different types of therapy.