Research > Focus A > Work Packages A04
Summary
Our project goal is to understand epigenetic and genetic mechanisms associated with temozolomide induced resistance in isocitrate dehydrogenase (IDH) mutant lower grade gliomas that exhibit promoter MGMT methylation. Our long-term aim is to reveal molecular targets that can be used in combination with alkylating agents to prevent the emergence of acquired resistance. The visual abstract below shows the aims and planned tasks of the work package.
Task 1
Characterize the evolution of molecular alterations during TMZ treatment
Steps / Workflow
- Generate TMZ resistant IDH mutant tumorsphere lines
- Analyze molecular state of cells generated in (1) during start of treatment, stress phase, and acquired resistance using next-gen sequencing (Whole exome, RNA-seq, and bisulfite-seq)
- Integrate sequencing data from (2) to identify candidate genes for Task 2
- Direct comparison of findings to N2M2 and AMPLIFY-NEOVAC cohort
Task 2
Determine the functional roles of the candidate drivers of resistance in vitro and in vivo
Steps / Workflow
- Generate cell lines with either stable knockout or overexpression of candidates identified in Task 1
- Generate inducible lines of select candidates to test efficacy in preventing resistance
- Intracranial implantation of select cell lines in NSG mice for vehicle/TMZ treatment
Task 3
Investigate the evolution of clonal substructure during TMZ treatment by single cell RNA-seq
Steps / Workflow
- Single cell copy number and transcriptional analysis of naïve and resistant tumorspheres, and matched primary and recurrent IDH mutated tumors
- Data analysis to determine clonal heterogeneity due to TMZ treatment
TURCAN, SEVIN, PH.D
University Hospital Heidelberg, Department of Neurology, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
Address
Im Neuenheimer Feld 400
69120 Heidelberg
Themen
Research
- Focus A
- A01: Targeting tumor cell networks to overcome primary and adaptive resistance in glioblastoma
- A02: Development of a specific combination therapy for histone H3-mutant pediatric glioblastoma
- A03: Deciphering resistance against targeted treatments
- A04: Evolution of IDH mutant gliomas during malignant progression
- A05: Predictive biomarkers for MGMT-promoter-methylated glioblastoma
- A06: Resistance mechanisms of glioblastoma against alkylating agents and radiotherapy
Research
- Focus B
- B01: Mechanisms of response and resistance to checkpoint blockade in gliomas
- B02: DNA mis-match repair regulates immune checkpoint blockade therapy in glioblastoma
- B03: Targeting immunosuppressive programs in isocitrate dehydrogenase mutant gliomas
- B04: Impact of myeloid cells on the adaptive immune response in IDH1-mutant glioblastomas
- B05: Dissecting the response of glioblastoma and its tumor microenvironment to focused high-dose radiotherapy
Research
- Focus C
- C01: Comprehensive preclinical pharmacology testing of drugs used for glioblastoma treatment in children and adults
- C02: Radiomics, radiogenomics and deep-learning in neurooncology
- C03: Imaging immune signatures of glioma response and resistance towards immunotherapy
- C04: Identification and spatial mapping of metabolic resistance factors by MALDI mass spectrometry imaging
- C05: Overcoming glioma radio-resistance with particle therapy