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Work package 01

Individual radiosensitivity

To study the biology of tumour response to radiotherapy using preclinical models and large high quality clinical material and applying techniques looking at DNA, RNA, and protein level in order to identify factors that can form the basis for individualized therapeutic intervention.
Description of work
Task 1.1. Characterizing tumour microenvironment. There can be substantial heterogeneity in the tumour microenvironment conditions (e.g. oxygen concentration, metabolism, and blood supply) between individual patients which can be associated with different response to radiotherapy. Using molecular profiling analysis on preclinical studies (cell lines and mouse xenograft models) and retrospective and prospective clinical material, biological markers that can characterize the heterogeneity of tumour microenvironment conditions will be identified.
Task 1.2. Predicting response to targeted therapies. Modified treatment regimes designed to overcome problems of hypoxia and proliferation may be associated with increased risk of morbidity, and it is therefore of outmost importance to identify patients where hypoxia and/or proliferation is prominent and where intervention will affect outcome. Furthermore, if present possibilities for modifications can be predicted to be inadequate in a given patient, other treatment modalities (i.e. surgery) could be advisable. Using molecular profiling analysis on retrospective and prospective clinical material, biological markers for predicting outcome of targeted therapies against hypoxia, EGFR, and tumour vasculature will be identified.
Task 1.3 Predicting risk of radiation-induced morbidity. Risk of radiation-induced morbidity, particularly late morbidity like radiation-induced fibrosis, is an important factor for intensification and individualization of radiotherapy due to its influence on quality of life of long term survivors of radiotherapy. The risk of radiation-induced morbidity varies between individuals and has a genetic component. Genetic variations associated with risk of radiation-induced morbidity will be identified based on preclinical studies (fibroblast cell lines), preclinical models (mouse models) and genetic association studies in large retrospective clinical material. Part of this task in done within the framework of GENEPI (Genetic pathways for the prediction of the effects of irradiation) - European normal and tumour tissue bank and database, ESTRO (The European Society for Therapeutic Radiology and Oncology).
Deliverables (projected outcome)
D1.1 Identification of novel biological markers for characterization of tumour microenvironment conditions. These markers can be patient or tumour specific changes on RNA or protein level or other molecules or processes that can reflect the heterogeneity in tumour microenvironment conditions.
D1.2 Identification of novel biological markers that can predict response to targeted therapies. These markers can be patient or tumour specific variants or changes in copy number of DNA, mRNA or miRNA expression patterns, or protein expression/modification patterns.
D1.3 Identification of genetic factors associated with risk of radiation-induced morbidity. These factors can be germline DNA variations like single nucleotide polymorphisms (SNPs) or copy number variants.

Workpackage leader: Jan Alsner, AUH

Involved scientists:
Brita Singers Sørensen, AUH
Isabel Nawroth, AU
Kasper Toustrup, AUH
Filippo D'Andrea, AUH
Trine Grantzau, AUH
Pernille Lassen, AUH
Trine Tramm, AUH