Vloga genetskih polimorfizmov na izid zdravljenja in pojav zapletov pri otrocih z rakom (Slovene)

Although an enormous progress was achieved in the survival rate of childhood cancer, still in some 40 % of all cases the outcome is fatal. A possible way of further improvement is individualization of treatment protocols by distinguishing patients with better tolerance of high dose chemotherapy from those who are more prone to severe toxic events in advance.   Vincristine, a chemotherapeutic agent, is widely used in combination with other agents in the treatment of pediatric haematological malignancies and solid tumors. The most established mechanism by which vincristine inhibits tumor growth is its interference with mitotic spindle microtubules resulting in inhibition of mitosis. Patients treated with vincristine predictably develop peripheral neuropathy which is a major dose-limiting side effect of vincristine. In children treated with identical treatment protocols containing vincristine, the severity of peripheral neuropathy varies greatly. Peripheral neuropathy may be related to polymorphisms in genes involved in vincristine pharmacokinetics or pharmacodynamics: metabolising gene or vincristine toxicity related genes.   Every year we diagnose around 60-70 new patients with childhood cancer in Slovenia. In two years we expect to include around 90 patients with vincristine regimen in their treatment protocol. In all patients we will monitor all possible acute toxicities. In our study we will stratify patients based on signs of standardised clinical neurological examination and parameters of standardized electrophysiological examination according to the severity of vincristine induced peripheral neuropathy. We will genotype DNA from mononuclear blood cells for polymorphisms of vincristine metabolising gene (CYP3A5) or vincristine toxicity related genes (MDR-1 and MAPT).   Based on the results of genetic polymorphism of target genes we expect that we will be able to predict the risk for development of peripheral neuropathy in children treated for cancer. These results may reveal subpopulation of patients with increased risk for peripheral neuropathy after the treatment with vincristine. We could also define group of patients, which may tolerate higher doses of Vincristine in whom intensification of vincristine chemotherapy regime may improve survival of children treated for cancer. The final perspective of all pharmacogenetic studies is therapy individualization. By finding a patient-specific “optimal” dose, we could balance the risk of relapse and the risk of severe adverse effects more precisely.

Pharamacogenetics is a quickly improving field of molecular genetics. The individual differences in the drug metabolism, pharmacokinetics and pharmacodynamics contribute to the efficacy and safety of any pharmacotherapy. Since in hematology and oncology very toxic and predominantly high-dose chemotherapy regimens are used, pharmacogenetics can provide useful information for better patient care. With the results of our research project we followed the trends and came closer to personalised therapy of children with cancer. Altogether, we published more than 30 peer reviewed papers in journals indexed by SCI. Also, three members of our research group successfully finished their doctoral thesis.

With the successful international collaboration we managed to transfer top science to our research community. We developed a research infrastructure which include top foreign scientists and enable us to collaborate in everyday clinical decision making as well as in developing future research strategies. We contributed to interdisciplinary research on the pediatric oncology field. Importantly, we claim that the results of our research project have a direct effect to improve the care of children treated for cancer on The department for pediatric hematology and oncology of The University Pediatric Hospital in Ljubljana.