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Clinical radiobiological factors

Research area 1

Tumour sensitivity
Modified treatment regimes designed to overcome problems of hypoxia, proliferation, and intrinsic radioresistance may be associated with increased risk of morbidity, and it is therefore of utmost importance to identify patients where specific interventions 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. We will therefore study the biology of tumour response to radiotherapy using large high quality clinical material and applying techniques looking at DNA, RNA, and protein level (WP01*), supplemented by non-invasive imaging methods like PET (WP02, WP04), in order to identify factors that can form the basis for individualized therapeutic intervention.
As an example, it has previously been demonstrated that mainly tumours which overexpress the epidermal growth factor receptor, EGFr, benefit from the intensified (accelerated) radiotherapy. The Zalutumumab, an inhibitor of EGFr has been introduced in a randomized clinical trial, DAHANCA 19, which started in 2007. So far, there is no clear indication for which patients with squamous cell carcinoma of the head and neck (HNSCC) will benefit from EGFr inhibition and there is most likely interaction(s) between hypoxia and proliferation which could be affected by EGFr-blockage therapy.
In ongoing pre-clinical studies we are currently characterizing known, and identifying new, genes/proteins that are potential endogenous markers of hypoxia. Some of the known potential markers include CAIX, OPN, HIF1α, and LOX. These will be tested (WP01, WP02, IP01) in our extensive clinical material from the unique DAHANCA 2 and 5 trials, where patients were randomised to receive the hypoxic radiosensitizer, nimorazole. Only in such randomized trials is it possible to evaluate markers for their ability to identify patients that will benefit from hypoxic modification. As proof-of-principle, we have previously found that the benefit of nimorazole is restricted to patients with high levels of plasma osteopontin, OPN. However, measurement of OPN alone is not sufficient to predict, on an individual basis, those patients that contained clinically relevant hypoxia and would benefit from hypoxic modification, thus the need to find other markers. Our preclinical studies are therefore also designed to identify novel potential markers of hypoxia using gene expression arrays and proteomics studies. Once these have been identified and characterised, they will be tested for their potential as predictive markers for hypoxia in our clinical material.
Besides tumours of the head and neck, the project will also include studies on breast and other cancers (WP01, IP03). A central part of the studies will be performed on DNA and RNA from paraffin embedded material. A collaboration has been established with Siemens Medical Solutions Diagnostics which perform the DNA and RNA extractions.

Normal tissue morbidity
Biological factors involved in normal tissue morbidity (in particular radiation-induced fibrosis, RIF) will be studied in clinical material based on individual genetic profiles ('radiogenomics') (WP01). As an example, we have characterized the overall transcriptional response in fibroblasts to ionizing radiation, and now have gene expression signatures in irradiated fibroblasts which predict risk of RIF.

* WP and IP numbers refer to the workpackages and intervention protocols in which the research takes place.