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EUROXY Report Summary

Project ID: 502932
Country: Denmark

Final Report Summary - EUROXY (Targeting newly discovered oxygen-sensing cascades for novel cancer treatments Biology, equipment, drug candidates)

The EU research project EUROXY had 21 academic research groups and both small and medium size companies. The consortium did pre-clinical research on new ways to detect and treat solid human tumours and developed new equipment. Solid tumours have central areas were the network of blood vessels is sparse and/or malfunctioning and where therefore both the oxygen tension is low (hypoxia), the pH is low and the concentration of nutrients is low. This microenvironment makes the cells less susceptible to ionizing irradiation therapy and often also to chemotherapy.

To survive the abnormal environment tumour cells adapt by a number of mechanisms. It was the working hypothesis of the EUROXY consortium that interference with these adaptive mechanisms might represent a new way of detecting and treating solid tumours. The consortium in its five year long period of function carried out basic molecular biology research whereby adaptive pathways were identified as were molecules with prognostic value and a potential as targets for detecting / imaging of hypoxic tumour tissue and for therapeutic targeting. These included new targets of HIF, of HIF hydroxylases, as well as molecules involved in UPR and mTOR pathways and in autophagy.

On the basis of these results, we detected gene expression patterns of hypoxic tumour tissues yielding information about disease progression / prognosis as tested on clinical material. We also found evidence that a Carbonic anhydrase (CA IX) molecule shed by the hypoxic tumour cells into the blood may be found useful for non-invasive monitoring of tumour progression. New imaging of hypoxic tumour tissue was developed using labelled CA IX-selective inhibitor, and we proved in principle its clinical usefulness in scanning / imaging the extent of hypoxic tissue in a tumour, as a guide on differential irradiation dosing within a tumour.

Animal studies of human tumour cells grafted to mice using putative anti-cancer drugs revealed an important metastasis inhibiting effect of a compound that works best a moderate hypoxia (bioreductive compound). Another compound CA9i, an inhibitor of the enzyme involved in regulation of pH, also showed promise as an inhibitor of tumour growth in animal experiments when used alone. It will probably find its clinical use in combination with other compounds interfering with the tumour cells control of their acidity. Even an antibody to the CA IX target showed therapeutic potential.

An unexpected finding was a high killing of cultured tumour cells when simultaneously exposed to low does rate irradiation and hypoxia, suggesting a new type of irradiation treatment. In parallel with these developments a number of companies brought forward different products for the commercial market. The companies were to a large degree inspired by the basic biologic research of our consortium. The final products were a combined mini clean room and incubator, a new type of combined incubator and fermentor allowing complete control of the oxygenation of cells grown in culture, two types of oxygen sensing culture flasks one with strip the other with chip sensors built into the flasks. Finally two red-ox sensors based on two different measuring principles were brought to marketability by two different developers.

In short, the EUROXY consortium got pre-clinical results that will be brought to clinical testing in a follow up program METOXIA also supported by the European Union (EU). In addition, new equipment was developed and brought to the commercial market.

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