Background and objectives
New methods to detect cancer micro-environmental parameters are developed alongside new therapeutic principles in the form of chemicals as possible new chemotherapeutic drugs and new methods to improve radiotherapy. The article below was published in the Public Service Review, European Union, Issue 20, 2010, ISSN 1472-3395, p.188-189.
METOXIA: Translation of new knowledge into cancer detection and -treatment
Erik O. Pettersen, METOXIA Scientific Co-ordinator here looks at the background and main aims to improve cancer diagnosis and -treatment within this large-scale FP7 Collaborative Project.
The METOXIA consortium consists of 19 universities, research institutes and hospitals, 2 small and medium sized companies (SMEs) and 1 larger company, i.e. 22 partner groups in total, from 11 European countries. A broad range of expertise is involved, from major cancer clinics, to expert fundamental researchers within biology, chemistry, medicine, physics and electro-engineering. New methods to detect cancer micro-environmental parameters are developed alongside new therapeutic principles in the form of chemicals as possible new chemotherapeutic drugs and new methods to improve radiotherapy.
METOXIA builds on an integrated project of FP6 denoted EUROXY. This project, which run from 2004 to 2009 was co-ordinated by Professor Peter Ebbesen of the University of Aalborg, Denmark. A large part of the METOXIA partners were also partners of EUROXY. During the EUROXY project collaboration was initiated to start development of most of the principles that are continued in METOXIA.
Background and some history
The common denominator of the METOXIA project is the hypoxic micro-environment of the solid cancer. A little background is necessary to understand the aims of the project.
The micro-environment in solid cancer tumours is highly variable due to variable vascularisation. As a result the oxygen concentration varies enormously due to cell respiration and low diffusion-rate of oxygen. This was first indicated as a possible problem in radiotherapy of cancer almost 80 years ago through observations made by Crabtree and Cramer in 1933 and Mottram in 1936, and was fully identified by Gray and co-workers in the 1950s. Their scaring observation was that cancer cells in solid tumours with little or no oxygen (hypoxic cells) could tolerate about 3 times higher radiation dose than normal cells which are well oxygenated. For several decades thereafter this micro-environmental characteristics of solid cancers were studied primarily by radiobiologists with the aim to improve radiotherapy through development of techniques or drugs to increase radiosensitivity specifically of hypoxic cancer cells.
Over the last 30 to 40 years it has been recognized with steadily increasing acceptance within both cancer research in particular and cell biology in general, how sweeping the influence of variable oxygenation is on cell behaviour. Even very small and transitory down-regulations of the oxygen concentration is sensed by specialised molecular sensors (the key substance is denoted HIF: Hypoxia-Inducible-Factor) which regulate the expression of several genes in the genome inducing signal substances trigging processes in other cells, including those that are not hypoxic. For example, one type of cells that are stimulated by this process is the so-called endothelial cells which form new blood vessels thereby tending to increase the blood supply. Several other processes are influenced by HIF, for example processes that select cells to live or die during the formation of a foetus. When the oxygen concentration drops further down to concentrations where cell respiration is inhibited, other molecular sensors in cells are activated which halts cell cycle progression and cell division and thereby tends to protect the cells against damaging effects of the severe hypoxia. Thus, normal cells have regulatory processes to protect them against hypoxia itself and also to turn to account naturally occurring hypoxia in their normal activity. These regulatory processes are maintained and to some extent strengthened or changed in cancer cells which experiences hypoxia more frequently, over longer periods of time and to a more severe degree than most normal cells. As a consequence cancer cells in solid tumours develop in a direction which is dangerous for the patient: Their genome is unstable, their tendency to divide uncontrolled promotes selection of the fittest, and the hypoxic micro-environments increases selection towards ability to survive under hypoxic conditions. This has been shown to be a driver towards increased malignancy of the cancer cells. At the same time the original problem of treatment resistance as was indicated by the mentioned early radiotherapy has been shown to be far more general: It involves also resistance against many types of chemotherapy and furthermore, tumour hypoxia has even been shown to be a negative prognostic factor for surgery.
The major METOXIA objective
Over the last two decads or so an additional factor has added to the problems raised by tumour hypoxia. It has been shown that the oxygen concentration in the tumour varies up and down due to sudden changes in the tumour vasculature and that this may have an extra effect on the cancer cells which is severely negative for the patient: The variable oxygenation seems to induce over-replication of DNA in the cells and increase the ability of cancer cells to metastasize, i.e. to spread and form distant new tumours throughout the body.
This is the central point for METOXIA: While almost 40% of cancer is curable by surgery or radiotherapy of localised disease, treatment is largely palliative for patients after the cancer has formed distant metastases. Thus, in essence the most central theme in the METOXIA project is to develop methods to record hypoxic areas in patient tumours as well as new methods of treatment which can reduce the propensity of the cancer to metastasize.
The over-all idea is to translate the new knowledge concerning regulatory cascades initiated by tumour hypoxia to patient benefit. The term “new knowledge” is not restricted to what was known at the up-start of the project. On the contrary, new knowledge is gained throughout the project and several of the objectives aim to improve research within the field. For example, several partners of the consortium work on development of new technology to detect the amount of oxygen and oxygen-related reactive compounds in tissues and tissue cultures. This involves diagnostic approaches like MR- and PET-scan, but also new sensor technology and electronic equippment to transmit data. Furthermore, we develop new biological models specialized for studies of the mechanisms leading to increased metastases as well as improved treatment to inhibit this process. We also have a broad activity on the study of the molecular mechanisms leading to increased metastasis and regulation of formation of blood- and lymph vessels.
Still, the main characteristics of METOXIA parting this from the previous EUROXY project is the aim to develop new principles of diagnosis and treatment as far as to give proof-of-principle demonstration of the efficiency in clinics or as close to clinics as possible. This is a real challenge since it necessitates integrated collaboration between researchers of relatively distant fields. Furthermore, even this development is in most cases bringing us only part of the way to clinical benefit for the patient. Developing a new drug is extremely costly and can not be financed by governmental money as those involved in the FP7-programme. Although this is a large-scale project with close to 12 million euros in EC contribution the money can not finance development of any drug. Therefore, industry outside of this consortium must take over the development once we have proven a new principle to work. In order to finance such development this industri must see that there is a chance to earn back their investment. Thus, to fullfill our task, the METOXIA partners are urged to validate their discoveries with respect to commercialization under the comprehension that this is an important part of translational research. Such considerations are not always part of the traditional routines for researchers in the field of medicine. METOXIA therefore puts emphasis in the patenting of drugs which have a particular effect with respect to our main objectives or to evaluate other means of protecting new sensor technology or discoveries so that these are made interesting for development into practical use for the patient.