Clinical Cooperation Unit Neurooncology (Prof. Dr. Wolfgang Wick)

Research of the clinical cooperation unit (CCU) neurooncology has the overarching goal to more comprehensively understand the biologic mechanisms underlying glioblastoma and primary CNS lymphoma and their respective treatment resistance. We strive for the identification and validation of diagnostic, prognostic and predictive biomarkers for guiding clinical decision-making and ultimately develop new points/molecules for therapeutic intervention that are to be tested in follow-up clinical trials. The current and future focus of the research in the Neurooncology Clinical Cooperation Unit (CCU) is based on central research questions derived from Heidelberg University Hospital neurooncology program, with the clear aim of translating the pre-clinical observations back into the clinic in a bench-to-bedside approach.

The clinical cooperation unit (CCU) neurooncology has six distinct research foci:

• Molecular understanding of glioblastoma networks and the role of CHI3L1 herein. With the exciting discovery of multicellular glioblastoma networks a new concept of growth and resistance for brain tumors has been established. Aiming to decipher the molecular underpinnings of these networks we established a transcriptomic signature for connected glioblastoma cells through single cell and bulk RNA sequencing of in vitro and in vivo models as well as patient tissue from clinical studies. We identified chitinase-3-like 1 (CHI3L1), a molecular marker with functional relevance for tumor cell networks and potential therapeutic applicability, in glioblastoma and validated its significance. These discoveries have pathed the way for further follow-up projects on the exact mechanism of action of CHI3L1 and the relevance of other putative tumor network relevant genes.
• Biomarker identification and understanding mechanisms of resistance against targeted agents in glioblastoma. This discovery arm aims to unravel the molecular mechanisms of several targeted therapies such as Temsirolimus, an mTOR inhibitor, and Atezolizumab, an anti-PD-L1 antibody, but also to define pathways involved in acquired resistance, such as TP53 signaling for alkylating therapy. We also aim to understand the interaction between radiation and the molecularly defined treatments by analyzing patient tissue with omics technologies in the scope of the NCT Neuro Master Match (N2M2) umbrella trial for newly diagnosed MGMT unmethylated glioblastoma and other larger randomized trials coordinated by the clinical neurooncology unit.
• Liquid biopsy program for brain malignancies. This consists of a multiomics integrative approach including cytology, proteomics and ctDNA sequencing from cerebrospinal fluid (CSF). Harnessing proteomics has allowed grouping of glioblastoma patients into prognostically different clusters and identification of CSF biomarkers that are unique for glioblastoma compared to other brain malignancies. A cfDNA sequencing platform analyzing a panel of 170 brain tumor relevant genes was established and is currently capable of detecting mutations and copy number profiles in glioblastoma patients, potentially allowing a diagnosis without biopsy in difficult to biopsy conditions or tracing tumor evolution.
• Molecular fingerprints and phenotypic traits of glioblastoma stem cells.
• Development of immunotherapies for brain tumors. Immune checkpoint inhibitors, tumor vaccines as well as CAR-T cell approaches are current object of research to address glioblastoma-enriched or specific targets in both the primary and recurrent setting. Specifically, we investigate intervention therapies for PD-L1, IDH1 R132H, and additional drug targets upregulated after standard of care therapy.
• Characterization of primary central nervous system lymphomas (PCNSL). In previous studies we have applied unbiased genetic approaches (Whole Exome/Genome Sequencing, 850k analysis, among others) to PCNSL specimen in order to define molecular hallmarks of CNS lymphomagenesis. Yet many detected alterations remain incompletely understood. Findings are therefore modeled in lymphoma cell lines in vitro and in vivo using xenograft models. The latter allows to uncover the phenotypical and molecular consequences of various genetic alterations. In vitro drug screens and CAR-T cell engineering allow to guide novel targeted therapies, that are initially evaluated in a preclinical mouse model, with an aim for translation into early clinical trials.

Our CCU Neurooncology is strongly linked to the CCU Neuroimmunology and Brain Tumor Immunology (D170), CCU Neuropathology (B300) and has vital collaborations to the Department of Hematology, Oncology, and Rheumatology as well as to the experimental imaging departments at both the Head Clinic and the DKFZ. Moreover, close collaborations exist within the UNITE glioblastoma consortium (https://www.unite-glioblastoma.de/). Integration into a national as well as international network additionally strengthens and is of utmost importance for the rapid transfer of research results to the clinic.