Projects / Programmes
TRANS TIO
Translational pharmacogenomic research of thiopurine therapy
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| B200 |
Biomedical sciences |
Cytology, oncology, cancerology |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
Pharmacogenetics, Therapy individualization, 6-mercaptopurine, acute lymphoblastic leukemia, drug toxicity, thiopurine S-methyltransferase, S-adenosylmethionine
Researchers (10)
Organisations (2)
Abstract
The proposed project is the result of longstanding continuous effort and the international cooperation of academics and clinicians in an effort to individualize the treatment of childhood acute lymphoblastic leukemia (ALL), thereby further improving its efficiency and safety, and to implement novel findings in the thiopurine therapy of other pathologies.
ALL therapy has evolved immensely over the last decade, resulting in almost complete remission; however, only 75-80% of patients are cured. Recent advances in pharmacogenomics have enabled the design of individualized ALL therapy that is based on a correlation of an individual’s responses to thiopurines and polymorphisms in Thiopurine-S-methyl-transferase (TPMT), the main 6-MP deactivating enzyme in hematopoietic cells. Hence, patients with decreased TPMT activity have a higher incidence of 6-MP-related toxic side effects. Recent findings include other factors influencing thiopurine metabolism and transport, as well as target molecules and signal pathways through which 6-MP exerts its activity.
Based on state-of-the-art in the field and our own contribution and advances we have identified the following challenges:
I. Insufficient efficacy and safety of thiopurine therapy
II. Low bioavailability of thiopurines, resistance and drug interactions
III. Insufficient implementation of pharmacogenomic knowledge in clinical practice
We are confident of meeting the challenges with clearly defined aims that will be pursued with the help of modern experimental approaches and a multidisciplinary group of experts.
AIM 1: Identification of novel factors influencing TPMT activity
The utilization of contemporary high-throughput techniques for the analysis of genomic, transcriptomic and metabolomic data will enable the identification of key parameters, delineating the molecular mechanism of the thiopurine-related response.
AIM 2: Identification of markers that affect the response to thiopurines
The utilization of in vitro lymphoblastoid cell line (LCL) models will allow for the identification of biomarkers contributing to resistance or (over)sensitivity to thiopurines and, consequently, to therapy outcomes; these biomarkers will be confirmed in a retrospective study on pediatric ALL patients.
AIM 3: Evaluation of novel biomarkers in the Slovenian ALL patient population and the development of dosing algorithms for 6-MP treatment
Newly identified biological markers will be evaluated in both retro- and pro-spective studies. Based on the correlation of these biomarkers with 6-MP, optimal-dose dosing algorithms will be designed.
AIM 4: Validation of dosing algorithms in independent populations of pediatric ALL patients will be performed in independent populations of paediatric ALL patients in collaborating in Serbia and Sweden.
AIM 5: Development of software tools for the calculation of optimum dosage of 6-MP in pediatric ALL patients will facilitate the translation of basic research into clinical practice.
The proposed project has a direct impact on both the economy and society. The implementation of pharmacogenomics in clinical settings contributes to rationalized therapy involving fewer side effects and greater effectiveness, hence contributing to (a) the improved quality of life of patients undergoing the therapy, and (b) favorable pharmacoeconomic indicators including a saving in the health budget.
The proposed project is of high scientific relevance; despite its complexity, the successful implementation and completion of the project is guaranteed by the expertise provided by an international, interdisciplinary team including partners from UL FFA, (Prof. dr. I. M.-Raščan), Department of Pediatrics, University Clinical Center Ljubljana (dr. J. Jazbec), Estonian Genome Center of the University of Tartu, Estonia (dr. A. Metspalu), Tel Aviv University (dr. D. Gurwitz), Linkopig University, Sweden (dr. M. A. Linqvist), University of Belgrade, Serbia (dr. J. A. Stanković) and t
Significance for science
The study is an integral part of a recent initiative on pharmacogenomics at the Faculty of Pharmacy, University of Ljubljana, and shall thus contribute to the development of the pharmacogenomics discipline in Slovenia. By implementing it, we wish to establish a solid scientific and educational environment of the highest standard, and strengthen our research capabilities. The field of pharmacogenomics is becoming integrated in all aspects of research and development of medicines. In this project, we implemented these new achievements as well as contributed to the development of the field by defining the genetic basis of differences in inter-individual response to the therapy and by delineating the molecular mechanism of thiopurine induced apoptosis. Prof. Mlinarič-Raščan's primary research interest and teaching experience is pharmacogenetics, which is implemented into the in-house research group programme. This was an interdisciplinary project with cooperation of the Faculty of Pharmacy and the Pediatric clinic, Department of Oncology.
Significance for the country
Individualizirana medicina, ki vključuje individualizirano terapijo, je integralni del pobude za translacijske raziskave na Fakulteti za farmacijo, Univerze v Ljubljani, ki bo pripomogla k razvoju teh specialitet v Sloveniji. K temu pripomore tudi dejstvo, da je Slovenija postala polnopravna članica evropske raziskovalne infrastrukture EATRIS.ERIC ( European advanced transaltional research infrastucture). UL FFA je nosilec teh aktivnosti. Zaključen projekt TRANSTIO in raziskovalci na projektu aktivno prispevajo k tej izvedbi s pomočjo znanstvenih rezultatov in z organizacijskimi dejavnostmi. Z aktivnostmi v tej pobudi želimo vzpostaviti trdno znanstveno in izobraževalno okolje najvišjih standardov, prav tako pa tudi izboljšati možnosti za nove dosežke in prispevati k razvoju tega področja. Področje farmakogenomike v individualiziranih terapijah je raziskovalno in pedagoško področje prof. Mlinarič-Raščan, in raziskovalne skupine v kateri deluje. Izvedeni projekt je interdisciplinaren ter temelji na sodelovanju med Fakulteto za farmacijo in Oddelkom za onkologijo in hematologijo Pediatrične klinike, KC Ljubljana .
Most important scientific results
Annual report
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
2015,
final report
