GRK 2762 - Research Projects
Project L4Interplay of exosomal miRNAs and genomic alteration in radiation response modulation and use as prognostic factors in NSCLC
Principal Investigator
Prof. Dr. med. Martin Stuschke
Summary
Radiotherapy alters the release of exosomes and their load with a repertoire of non-coding RNAs, thereby modulating therapy outcome. Thus, exosomes and exosome-derived microRNA (miRNA) hold promise as predictive factors and therapeutic targets for modifying RT response. However, interactions of genetic, epigenetic and non-genetic factors in modulating the radiation response of molecularly heterogeneous non-small cell lung cancer (NSCLC) cells and patients are not completely understood and thus require further definition.
This project aims to perform functional analyses in a panel of heterogeneous lung cancer cell lines to define miRNAs as targets of radiosensitization and as prognostic markers of response for radiotherapy of NSCLC with various genomic alterations. The PhD project will study radiation-induced changes in the expression of pre-selected miRNAs known to affect sensitivity to cisplatin or irradiation as defined in the project, and explore the role of miRNAs with reported function in regulating the DNA damage response and radiosensitivity in a panel of molecularly defined cell lines representing clinically relevant NSCLC subtypes.
The project will closely collaborate with a clinician scientist project which will complement the functional studies with information from patient monitoring. The clinician scientist will use tissue samples and serial plasma samples collected from lung cancer patients receiving definitive radiochemotherapy without or with Durvalumab consolidation or re-irradiation before and during the course of radiochemotherapy, to profile exosome cargo for a large panel of miRNAs and their loading with PD-L1 (prospective register study, Dept. of Radiotherapy). Any miRNA found to be altered in patients before, during or after irradiation will be identified and monitored, and results will be correlated with patient treatment response and tumor mutational status obtained from extended panel sequencing.
Long-term goal is to evaluate the miRNA of extracellular vesicles released by cancer cells as biomarker and functionally characterize biomarker candidates on their effect on the radiation response. The overall goal is to identify factors that fulfill the prerequisites of a biomarker, differential expression from patient to patient, and changes in response to therapy outcome.
Selected Publications
Eberhardt WE, Pöttgen C, Gauler TC, …, Stuschke M. Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J Clin Oncol 2015; 33: 4194-4201.
Pöttgen V, Gauler T, Bellendorf A, …, M.Stuschke. Standardized uptake decrease on [18F]-fluorodeoxyglucose positron emission tomography after neoadjuvant chemotherapy is a prognostic classifier for long-term outcome after multimodality treatment: secondary analysis of a randomized trial for resectable stage IIIA/B non-small-cell lung cancer. J Clin Oncol 2016; 21:2526-2534.
Sak A, Grehl S, Engelhard M, et al. Long-term in vivo effects of cisplatin on gamma-H2AX foci signaling in peripheral lymphocytes of tumor patients after irradiation. Clin Cancer Res. 2009;15(8):2927-2934.
Guberina M, Sak A, Pöttgen C, et al. ERCC2 gene single-nucleotide polymorphism as a prognostic factor for locally advanced head and neck carcinomas after definitive cisplatin-based radiochemotherapy. Pharmacogenomics J. 2021;21(1):37-46.
Sak A, Kübler D, Bannik K, et al. Epigenetic silencing and activation of transcription: influence on the radiation sensitivity of glioma cell lines. Int J Radiat Biol. 2017;93(5):494-506.
Sak A, Stuschke M, Groneberg M, et al. Inhibiting the aurora B kinase potently suppresses repopulation during fractionated irradiation of human lung cancer cell lines. Int J Radiat Oncol Biol Phys. 2012;84(2):492-499.
M.Zernickel E, Sak A, Riaz A, et al. Targeting of BRM Sensitizes BRG1-Mutant Lung Cancer Cell Lines to Radiotherapy. Mol Cancer Ther. 2019;18(3):656-666.
Niedermaier B, Sak A, Zernickel E, et al. Targeting ARID1A-mutant colorectal cancer: depletion of ARID1B increases radiosensitivity and modulates DNA damage response. Sci Rep. 2019;9(1):18207.
Wang H, Perrault AR, Takeda Y, et al. Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Res. 2020;48(9):5200.
Mladenova V, Mladenov E, Scholz M, Stuschke M, Iliakis G. Strong Shift to ATR-Dependent Regulation of the G2-Checkpoint after Exposure to High-LET Radiation. Life (Basel) 2021; 11:560.
Murmann-Konda T, Soni A, Stuschke M, Iliakis G. Analysis of chromatid-break-repair detects a homologous recombination to non-homologous end-joining switch with increasing load of DNA double-strand breaks. Mutat Res 2021;867:503372.