Research > Focus B > Work Packages B07A
Summary
Work package B07A is associated to UNITE and funded from ressources outside of the Collaborative Research Center (CRC) 1389.
In this work package, we will investigate the resistance of pediatric high-grade glioma to commonly used radiotherapy. Radioresistance will be induced in a unique portfolio of immunocompetent mouse models and molecularly analyzed for tumor-intrinsic mediators and factors in the tumor microenvironment (TME). Identified players will be validated genetically and subsequently targeted in derived combinatorial trials. TME-related factors will be investigated in vivo and combined with a first-in-class inhibitor of the chemokine CXCL12. In a complementary approach, DNA Damage Response inhibitors will be used to overcome radioresistance by enhancing immunogenic cell death in vitro and in vivo.
Task 1
Identification of factors promoting radioresistance in pHGG
Steps / Workflow
- Cyclic re-irradiation of immunocompetent models to generate radioresistance
- Molecular analysis by RNA- and single cell RNA-sequencing
Task 2
Validation of potential mediators of radioresistance
Steps / Workflow
- Validation of identified factors via IHC and WB
- Further validation using genetic approaches
- Conduction of derived preclinical combination trials aiming to re-establish radiosensitivity
Task 3
Mechanism and optimization of overcoming treatment resistance by inhibiting the CXCL12-CXCR4 axis
Steps / Workflow
- In vivo inhibition of CXCR4 and/or CXCL12 using different RT fraction sizes
- Determine additional effects of VEGF inhibition
- Analysis of TME using FACS, histology and RNAseq
- Visualization of the vasculature in TME
Task 4
Enhancing the antitumor immune response by increasing radiation-induced mitotic catastrophe (MC)
Steps / Workflow
- Screen different combi-nations of dose fractionation and DDR inhibitors to enhance MC and immuno-genic cell death (ICD)
- Monitor MC and deter-mine DAMP profile (ATP, Cal-reticulin, HMGB1, type-I IFN)
- Confirm in vivo
PRINCIPLE INVESTIGATOR
Zuckermann, Marc, PhD
Group Leader
Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), German Cancer Research Center (DKFZ), Division of Pediatric Neurooncology, Preclinical modeling Group, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany