People and Projects
You are invited to get an overview on the neurooncology projects and the people who do everything to make them happen:
SFB 1389 UNITE
For people and projects, please visit the SFB 1389 UNITE webpage.
Heidelberg Research College for Neurooncology
Dr. Marta Cook, University Hospital Heidelberg, Department of Pediatric Oncology
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
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
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
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
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. Marilin Koch, University Hospital Heidelberg, Department of Neurology
Dissecting determinants of cell fate change in IDH-mutant gliomagenesis
IDH-mutations are known driver mutations of low-grade glioma and entail transcriptional and epigenetic alterations, which are mediated by the inhibition of chromatin modifiers by the IDH-mutation induced oncometabolite D-2-hydroxygluarate. With this study I aim to identify prerequisites of IDH-dependent gliomagenesis and factors involved in subsequent emancipation of tumors as well as stemness modulators in IDH-mutant glioma.
To dissect regulators of gliomagenesis, we will leverage a human astrocyte cell line with doxycycline-inducible expression of mutated IDH as a tractable system of malignant transformation. We will modulate gliomagenesis in this system by co-culture with a set of compounds targeting histone modification, DNA methylation and glioma-associated pathways. Marker expression changes upon treatment will be evaluated with qPCR and flow cytometry. Subsequent phenotypic and functional characterization will include in vitro chemosensitivity assays (cytotoxicity, clonogenicity and spherogenicity assays), transcriptome and chromatin analyses (RNA Seq, CUT&Tag), and in vivo tumor formation studies.
By using a chemical screen and thereby focusing on druggable targets, our findings could directly translate to clinical treatment of glioma patients. Additionally, this study could yield fundamental insights into the process of cell fate change during malignant transformation of astrocytes and for the acquisition of stem cell like properties of progenitor cell like cancer cells.
Dr. Fuat Kaan Aras
Assessment of Phosphorylated Signal Transduction Pathway Proteins in Glioblastoma
The aim of this research is to identify the phosphorylation status of signal transduction pathways in glioblastoma. Special focus will be on the mTOR pathway. Mass spectrometry will be established for this process. The rationale for this project is the idea, that the determination of pathway activity may be a very suitable parameter for targeted therapy and may well supplement current NGS-Sequencing based target identification. mTOR is a focus because preliminary results of research of our partners demonstrates an effect of temsirolimus treatment in patients with activated mTOR pathway.
Standard approach to determining phosphoproteins has been immunohistochemistry. However, specificity and reproducibility need improvement. Therefore, mass spectrometry will be established and employed for systematic assessment of phosphoproteins in glioblastoma specimens. This approach has been successfully used in many functional studies, however has not been transferred to clinical brain tumor settings.
We think that routine analysis of the phosphorylation status of key signal transduction pathway proteins will be a highly relevant diagnostic procedure in the future.
Hertie Network of Excellence in Clinical Neuroscience
Dr. med. Katharina Sahm, University Medical Centre Mannheim, Department of Neurology
Advancing neoepitope-specific vaccines in Neurooncology
My main focus in translational research is advancing of neoepitope-specific vaccines. We have already identified shared clonal neoantigens in gliomas such as mutant IDH1 or mutant histone-3. Neoepitope-specific peptide vaccines induced mutation-specific antitumor immune responses in preclinical models and patients. One major challenge is to ensure homing of peripherally activated immune cells to the tumor while retaining their effector function. In the current project phase, supported by the Hertie Excellence in Clinical Neuroscience fellowship, I investigate the immune modulatory effects of irradiation on the tumor microenvironment. In a preclinical model we could already show that low-dose irradiation enhances homing and effector function of tumor-specific immune cells. By further studying mechanisms of response to combined radio-immunotherapy, we will potentually be able to identify clinically meaningful therapeutic targets within the brain tumor immune microenvironment.
Dr. med. Philipp Sievers, University Hosptial Heidelberg, Department of Neuropathology
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
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.
Dr. med. Sophie Weil, University Hosptial Heidelberg, Department of Neurology
Developing treatments targeting brain tumor networks
Gliomas are malignant brain tumors characterized by highly aggressive growth due to early dissemination into the brain and treatment resistance. Using an in vivo multiphoton mouse model of human gliomas, we have uncovered a novel factor involved in glioma biology: Tumor Microtubes are cellular processes that promote tumor cell invasion and proliferation and connect human glioma cells to a tumor cell network [Osswald et al., 2015] that is integrated to neuronal communication via synapses [Venkataramani et al., 2019]. Tumor Microtube-mediated networks contribute to resistance against all standard therapies such as surgical resection, chemo- and radiotherapy [Weil et al., 2017]. First factors driving Tumor Microtube formation have been uncovered, but further treatment options need to be investigated.
This project aims to develop new therapeutics targeting Tumor Microtubes to reduce Tumor Microtube-mediated interconnection of tumor cells with the goal to decrease resistance against standard tumor therapy. We will focus on local therapies to implant in the resection cavity after surgical lesion.