FIGHTINGDRUGFAILURE

Priorities and Standards in Pharmacogenomic Research: Opportunities for a Safer and More Efficient Pharmacotherapy

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 Obiettivo del progetto (Objective)

'Pharmacogenomics is the scientific discipline that relates inter-individual variation in drug response to genetic variation. While there have been major advances in basic genomic knowledge and genotyping technologies, translation into clinical practice has been slow. It is essential we quicken the pace of translational research in pharmacogenomics - at present, we cannot define which patients are going to respond to drugs, and which patients are going to develop adverse drug reactions. In this ITN, our concerted action across the EU, in cooperation with US researchers will train young investigators and clinicians (14 ESR and 2 ER) to establish, evaluate and retrieve relevant genetic information from patients, and relate it to clinical outcomes of drug therapy. This will be achieved through sharing patient materials, performing pooled analyses, transfer of knowledge and skills across laboratories and provide access to high-throughput technology platforms between 5 academic (3 EU, 1 ICPC, 1 OTC partners) and 4 industry partners (3 EU, 1AC partner). This will enhance translational research, promote uniform drug treatment standards throughout Europe and worldwide, and improve the competitiveness of the EU in this emerging and exciting field.'

Introduzione (Teaser)

Patient response to drug treatment shows a broad range of variations. Pharmacogenomics research is addressing genetic and epigenetic differences responsible for the variations in therapeutic response.

Descrizione progetto (Article)

Despite major advances in drug treatment and therapy, it is still difficult for doctors to determine the right medication and dose for every patient. The chosen drug should be the most effective for a specific person and condition with the fewest possible side-effects. Genome variability has been recognised as a reason for the differences in drug response (pharmacogenomics).

The Marie Curie Initial Training Network (ITN) funded the http://www.fightingdrugfailure.net (FIGHTINGDRUGFAILURE) initiative to train young investigators and clinicians in pharmacogenomics. The training involved international collaborations in order to establish, evaluate and retrieve relevant genetic information from patients and relate it to clinical outcomes of drug therapy. This was achieved through sharing patient materials, performing pooled analyses, and transferring knowledge and skills across laboratories.

The project studied healthy women and the prediction of their risk to develop breast cancer as a consequence of using long-term hormonal treatment for the relief of menopausal symptoms. It involved personalised assessment for the risk of recurrence in patients who received the selective estrogen receptor modulator tamoxifen for the control of their disease. It also focusedon patients who received cytotoxic agents for the neoadjuvant treatment of breast cancer caused by BRCA1 mutation.

Rresearchers found that the HSD17B1_G gene allele protected women from developing breast cancer when they had used hormone replacement therapy for more than 10 years. In the case of tamoxifen treatment, they identified polymorphisms of the CYP2D6 enzyme (responsible for the formation of the active metabolite) as a clinical outcome predictor. Moreover, tumour-associated microRNAs miR-126 and miR-10a were identified as independent predictors for tumour recurrence. In the case of neoadjuvant treatment with cytotoxic agents, the underlying BRCA1 mutation was predictive of a favourable response.

The researcher also addressed aspects of safer pharmacotherapy for frequently used drugs. They included anticonvulsants, antiretroviral and chemotherapeutic compounds as well as glucocorticoids, all of which are known to cause severe side-effects. In addition, specific hepatic factors and cholesterol-associated pathologies were analysed to identify more potential drug targets. Systems biology techniquess revealed entire pathways for potential improvements to drug treatment.

Overall, FIGHTINGDRUGFAILURE proved that genetic polymorphisms have great potential as biomarkers to improve individualised treatment strategies. The newly acquired basic and specialised knowledge equipped 17 young investigators and clinicians for their future independent research.