Research > Focus B > Work Packages B04
Summary
In the last funding period, we observed profound differences in the efficacy of drugs targeting the tumor microenvironment (TME) of gliomas. Therefore, this project aims at studying larger series of TME-targeting drugs on glioblastoma organoids in a high throughput format on the global, spatial, single cell and functional level by multi-omics and bioinformatic analysis. This will help to predict effectiveness of TME-targeting drugs on a patient-individual level and to develop a platform for the future personalized testing of TME-targeting drugs alone or in combination with other types of treatment in glioblastoma. The visual abstract below shows the aims and planned tasks of the work package.
Task 1
TAM-targeting drugs in GB TOs
- Impact of TAM-targeting drugs on viability, chemokine secretion and cellular composition of GB TOs
Steps / Workflow
- Standardized generation of n >2000 GB tumor organoids (TO) per case
- Automated screening of a library of TAM-targeting drugs
- Single nuclei analysis to identify changes in TAM and tumor cell subsets
- Integrated analysis to select the top 5 drugs
Task 2
TAM-specificity of treatment effects
- Phenotypical and functional impact of top 5 TAM-targeting drugs on freshly isolated GB-educated TAMs
Steps / Workflow
- Isolation and treatment of GB-derived TAMs
- Phenotypical changes in cells (FACS, RNAseq) and supernatant (cytokines)
- M1-related functional changes (iNOS activity, phagocytosis)
- Ranking of top 5 drugs according to TAM-specificity
Task 3
Personalization, timing and combinatorial use
- Drug response of top 5 drugs
- depending on GB subtype
- during longitudinal disease progression
- impact on T cells
- Synergistic activity of top 3 drugs with RT, TMZ or immune checkpoint inhibitors (ICIs)
Steps / Workflow
- TO treatment of additional cases (n=20) summing up to n=30 cases; assessment of viability, cytokines and RNAseq based GB subtype
- Treatment of TOs from recurrent GB (n=10)
- T cell infiltration in TOs (staining) Co-cultures to assess T cell activation, T cell secretome, T cell killing
- Combinatorial TO treatment (n=5cases) readout: viability, transcriptome, T cell infiltration
Previous funding period
PRINCIPLE INVESTIGATORS
HEROLD-MENDE, CHRISTEL, PROF. DR. RER. NAT.
Professor for Experimental Neurosurgery, Division Head
University Hospital Heidelberg, Department of Neurosurgery, Division of Neurosurgical Research, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
WARTA, ROLF, DR. SC. HUM.
Post Doc
University Hospital Heidelberg, Division of Neurosurgical Research, Department of Neurosurgery, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany