Research > Focus A > Work Packages A06
Summary
In this project, loss-of-function screens will be performed to decipher the mechanisms of isocitrate dehydrogenase (IDH) wildtype glioblastoma resistance to alkylating agents and radiotherapy. Presence and activation of these mechanisms will also be confirmed on human glioma tissue, also with regard to intra-tumoral heterogeneity. We aim to overcome current therapy resistance and ultimately recurrence of glioblastoma. The visual abstract below shows the aims and planned tasks of the work package.
Task 1
Identification of drug targets to increase chemo- and radiotherapy sensitivity
Steps / Workflow
- (Epi-)genomic and translational characterization of recurrent and newly diagnosed glioblastoma samples with MGMT methylated or unmethylated promoter.
- Loss-of-function screen with or without temozolomide or high-dose irradiation.
- Selection of the best hits
Task 2
In vitro validation of the identified hits
Steps / Workflow
- Validation via CRISPR/Cas9 system (FACS, caspase assay,…).
- Confirmation of the phenotype using available inhibitors and selection of the most effective and selective one.
- (Epi-)genomic and transcriptional monitoring of the inhibition.
Task 3
In vivo preclinical studies of small-molecule inhibitors to target recurrent glioblastoma and increase current therapies sensitivity
Steps / Workflow
- Establishment of orthotopic PDX models (including monitoring of the genetic changes by high-throughput sequencing)
- In vivo test of the established combinatorial treatments from tasks 1 and 2
Task 4
Assessment of potential clonal selection of the combinatory treatment
Steps / Workflow
Verification of a potential clonal selectivity of the treatment by single-cell sequencing using
- IDH mutant mouse model
- Confetti mouse model
- Optical barcoding
PRINCIPLE INVESTIGATORS
GOIDTS, VIOLAINE, DR. BIOL. HUM.
Junior Research Group Leader
German Cancer Research Center, Junior Research Group Brain Tumor Translational Targets, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
SAHM, FELIX, PD DR. DR. MED.
Consultant
University Hospital Heidelberg, Department of Neuropathology, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany