Objective

Objective

Development of a new methodology based on an advanced molecular probe for early detection of DPD enzyme deficiency in oncological patients also enabling a personalised and efficient drug management.

Background

Innovation

Background

Cancer  is the most common cause of death in Europe, with around 3,2 million new cases and 2 million deaths each year, with an increasing trend, as reported by WHO. It’s the therapeutic approach used to fight this plague that is casting a doubt on the severe side effects of chemotherapy. Amongst all the chemotherapy agents, 5-FU (fluorouracil) is being in use since 40 years, and is one of the most successful and widely employed in the treatment for breast, colon, and skin cancer.  In general, 5-FU is relatively well tolerated at standard doses, but there are some important issues that must be duly taken into consideration:

•  Around 8% of patients manifest a genetic variation that leads to a deficiency of an enzyme called Dihydropyrimidine dehydrogenase (DPD) that is crucial for the metabolism and deactivation of 5-FU. This causes several toxic reactions like mucositis, diarrhea, neutropenia, cerebellar ataxia, cerebellar dysfunction, and can even be fatal at the very first dose of 5-FU, with  a mortality rate of about 0,5%. This deficiency must be properly identified before the beginning of the therapy.

•  About 30% of patients suffer from severe toxicity effects after being treated with 5FU.

•  Despite many approaches have been proposed for DPD deficiency screening, none of the current strategies is adequate to mandate routine DPD testing prior to starting a 5 FU based therapy

Surprisingly enough, many works has found out that lots of patients are not being treated with the appropriate doses for achieving optimal 5-FU plasma concentration.

•  Only 20 – 30% of patients are treated in the optimal dose range;

•  Approximately 40-60% are underdosed;

•  Approximately 10-20% are overdosed

THE COMPETITIVE ADVANTAGE

If DPD deficiency is so dangerous, why isn’t there any approach mandatory to detect it? And, if a dynamic management of the therapy is more effective and less harmful, why is it so difficult to proceed this way?

Because currently there is not a standard, simple, fast, reliable, and cheap way to detect the DPD activity level, which also allows to calibrate the therapy following well established clinical algorithms. This revolutionary approach would be employed in every medical center dealing with cancer, and would allow to greatly enhance the effectiveness of the therapy, with enormous savings for the Healthcare Systems and, most importantly, safeguarding the priceless value at stake: the patient’s well-being.

Innovation

The novelty of the proposed approach to measure the DPD activity relies on the use of a “molecular probe”, perfectly analogous to 5-FU, which interacts with the DPD in the blood in the same way as 5-FU. The operating principle of the CARESS system relies on the researches performed by the selected RTD performers CNR and ICO.

The protocol will be automatized in the first, compact, cheap, accurate and standard system for measuring the DPD activity, thus allowing for fast screening of DPD deficiency; this will be the immediate short term result deriving from the project.

Expected Results

The competitive advantage that the enterprises will gain from the CARESS product will be ensured by the following system features:

•  Faster response time with respect to the best alternative on the market: the CARESS methodology will provide a response in few second, against the longer processing times of other available techniques (Mass Spectrometry);

•  Determination of DPD activity level without administration of a 5-FU test dose to patients;

•  The CARESS system will need only few ml of blood sample;

•  The use of simple procedures and of instruments widely available for routine clinical practice;

•  Before entering the therapy, the patient is routinely screened for DPD deficiency (currently not done);

•  The DPD level measured is used to calibrate the therapy for the next infusion, according to clinically validated algorithms.

The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013), managed by the REA - Research Executive Agency under the Grant Agreement n° 315398