The availability and accessibility of clinical samples is essential for the MSTARS project and handling clinical samples involves legal considerations. Thus, MSTARS comprises two work packages that focus on accessibility and distribution of clinical samples, establishment and maintenance of a clinical database, and coverage of all medical and legal aspects.
Clinical Sample Management
The lab of Ulrich Keilholz focuses on a deep molecular characterization of tumor entities to gain knowledge about the molecular basis of primary and secondary resistance to targeted treatments in order to inform the clinical precision oncology programs of the Charité Comprehensive Cancer Center. The team comprehensively analyzes tumor tissue on the genomic (next generation sequencing), transcriptomic (bulk and single cell RNA sequencing) and protein level to map signal transduction pathways as well as spatial and temporal changes. By that, they shed light on the clonal evolution of cancers and generate profiles of molecular adaptation to targeted treatments. In addition, the group studies treatment responses in patient-derived PDO models with the aim to identify new therapeutic strategies, especially combination therapies aimed to overcome adaptive resistance. Furthermore, they evaluate advanced disease monitoring tools, such as liquid biopsies, as a source for the identification of new biomarkers for treatment responses analyzing circulating tumor cells or cell free DNA.
ogether with the Klauschen lab, the team of Ulrich Keilholz recruits patients for the MSTARS consortium, organizes the clinical documentation, and harvests and pre-analytically processes the samples. Two databases are established, with one covering the MSTARS patient cohorts following a coding convention and the other covering sample information, guaranteeing consent management, but does not contain personal data. The prospective sample material as well as retrospective flash-frozen and FFPE samples are processed routinely following the molecular diagnostics protocols of the institute for pathology. For frozen tissue samples, the tissue composition is evaluated by cryo-section screening, subsequent FFPE embedding and quantitative machine learning-based image analysis. The establishment of a systematic and standardized workflow to measure the tumor, inflammatory and stroma cell content, guaranteeing a robust and comparable sample quality, is one important aim of the work package and will be, apart from HNSCC, expanded to other tumor entities.
The work of Ingeborg Tinhofer-Keilholz lab focuses on the molecular characterization of tumors and the analysis of resistance mechanisms, specifically in head and neck cancers, with the aim to shed light on the molecular basis of therapy resistances and to identify new target structures for molecular therapies. The group uses preclinical cell culture models for experimental drug treatment or radiation, and validates their findings in patient samples in the context of clinical studies. In addition, the Tinhofer-Keilholz lab has long-standing expertise in the generation of patient-derived 3D preclinical models and their characterization by next-generation sequencing.
They also use liquid biopsies as new diagnostics tool to follow up therapeutic responses and for an early diagnosis of tumor progression.
As part of the MSTARS consortium, the Tinhofer-Keilholz lab generates and expands organoid cultures of HNSCC. On the one hand, they use patient-derived PDX models to generate secondary organoid cultures and on the other hand, directly derive PDO cultures from patient material. The cultures are used to characterize tumors under steady-state conditions and upon treatment with molecular substances, and are distributed among the different work packages for multi-omics analyses. Finally, organoid cultures will be generated and expanded for other tumor entities.