The Apotherapy project: European science towards cancer therapy
Most of us know of someone whose life has been affected by cancer. Despite advances in medical research over recent decades, the disease remains a principal cause of death in developed countries, causing almost 1 in 5 deaths in the European Union.
The term ‘cancer’ covers a range of disorders, all of which involve uncontrolled division of cells or ‘building blocks’ of the body. These cancer cells can grow to form a tumour in the body and in some cases they may travel to another site in the body to form secondary tumours by metastasis.
Today, specific treatments are available for individual types of cancer and this progress over recent decades means that today more people are surviving in the short term after cancer diagnosis. However, these existing treatments, including chemotherapy and radiotherapy, are often not a long term cure and their side effects have a huge impact for the lives of cancer sufferers.
With increased life expectancy in the European Union and a swelling forecast in the over-50 age group of the population in European countries, it is essential to continue to tackle the problem of cancer and search for therapies with greater efficacy and minimal side effects. The European Union periodically invites proposals for funding from researchers willing to develop scientific research on a cooperative basis between EU countries.
Apotherapy is one of the projects funded by the Framework Program 6 (FP6) of the European Commission for Life Sciences & Health. It is a collaboration of research between experts from 7 European countries including scientists involved in basic research and biotechnology as well as oncologists, whose day to day work brings them in contact with cancer patients in hospital clinics. Apotherapy was designed specifically to draw on the talents of each research team involved to create and test new anti-cancer agents that will be applicable to a wide range of tumours, with minimal side effects.
The project is based on a protein, CD40, which is found naturally but at low levels at the surface of different types of normal cells within the body. The role of CD40 varies according to its expression but it is known, for example, to play an important role in orchestrating the body’s response to pathogens, such as viruses and bacteria. Studies on CD40 have revealed how this molecule can drive a form of controlled cell death called apoptosis in tumor cells. Cell death and its control are critical function for the body, as the removal of damaged cells is essential for the health of the organism. CD40 is also known to activate the body’s natural defence against cancer cells, a complex process known as anti-tumour immune response.
CD40, however does not perform these functions at all times. It must instead be activated when required, by its partner or ligand, CD40L. The function of a ligand is to bind to its target molecule and this commences cascades of cellular events which can have various outcomes for the cell, including its own death.
The qualities CD40 displays make it an ideal candidate for the basis of a novel and potentially powerful multi-faceted anti-tumour tool. Apotherapy will design state of the art synthetic microscopic carriers to deliver signals (CD40L) which will trigger CD40 naturally expressed on the tumour cell surface (see Figure 1 in Powerpoint format
). Scientists in Novosom AG, Germany, will be developing these liposome ‘messengers’ in a manner whereby they are attracted to the tumour mass. This efficient system is termed ‘targeted gene delivery’ and it offers a way of selectively directing the cancer therapy to exactly where it is required, leaving the surrounding normal tissue unaffected by the treatment.
These synthetic messengers are not the only manner in which we are able to exploit CD40 to kill cancer cells. In Finland, Greece and Sweden, experienced scientists working under the guidance of Drs Hemminki, Eliopoulos and Loskog, respectively, will be working to create viruses which can deliver the CD40 ligand gene to tumours. Researchers use a common cold virus, which has been modified in the laboratory so that unwanted viral genes are taken out and CD40L is inserted into the genes of the virus. In this way, a recombinant CD40L adenovirus acts as a trojian horse, being engineered to gain entry to the cell and to deliver our gene of interest, the trigger for CD40. Once inside the tumour cell, CD40L is ‘expressed’ or manufactured and the fate of the tumour cell is sealed; scientists hope to unravel the complex repercussions of CD40-induced cell death. It is hoped that the contribution of the activated immune system will prove critical for tumour eradication within the body, as our immune cells actively seek out and destroy any tumour cells still alive (see Figure 2 in Powerpoint format
A team of histology scientists led by Dr Ehrmann in the Czech Republic will be responsible for analyzing at the cellular level the effects of CD40 activation on the tumour and surrounding area. This work is essential in that it will document and confirm what is happening inside the living body in the short and long term when CD40L-treatment is given. Regression of tumours alone is not an adequate goal for scientific research; it is vital to understand not only what is happening when a cancer therapy is given but also how it happens.
With this in mind, teams of researchers in Italy and UK led by Drs Broginni and Falasca respectively, will be investigating how CD40 triggering can be made more efficient (see Figure 3 in Powerpoint format
). Part of the tightly regulated control of normal cell death involves a variety of ‘brakes’ which override death signals and act to prevent CD40 inducing cell death under normal circumstances. In short, the cell must remove these brakes if the death pathway is allowed to proceed. Central to the development of CD40-based therapy then, is a detailed analysis of what these inhibitory pathways are and how they act. The development of antagonist chemicals which can release these brakes is essential if we wish to observe CD40 unleash its full potential as a tumour treatment.
On a day to day basis each team of scientists is lead by its principal investigator and the project as a whole is coordinated by the head of the Greek team, Dr. Aristides Eliopoulos. The Apotherapy consortium of scientists, clinicians and researchers will meet together yearly to review in detail the progress of each team. Targets for research have been planned and we hope to not only reach these goals but to go further towards bringing this basic scientific research closer to the patients who need it. Towards the end of the three year funding period we will seek continuation of funding from the European Commission with the hope of bringing CD40-based therapy into clinical trials.
Apotherapy: ‘CD40 ligand-based modalities for the treatment of solid tumours’.
Contract number: 037344
Total cost: € 2,110,263
Commission funding: € 1,895,900