L3-8203

Serumski, genetski in epigenetski označevalci tveganja za nastanek, napredovanja in odgovora na zdravljenje bolezni povezanih z izpostavljenostjo azbestu

Serum, genetic and epigenetic markers of risk for developing, progress and treatment response in asbestos related diseases

OPIS PROJEKTA

Bolezni, povezane z izpostavljenostjo azbestu, še vedno predstavljajo velik problem v Sloveniji in tudi drugod po svetu. Izpostavljenost azbestu je povezana z razvojem azbestoze, boleznimi plevre, kot so plevralni plaki, difuzne zadebelitve plevre in plevralni izliv, ter z več oblikami raka. Ena najhujših in najbolj agresivnih azbestnih bolezni je maligni mezoteliom (MM). Uporaba azbesta je bila v Sloveniji zakonsko prepovedana leta 1996, a zaradi dolge latentne dobe in obremenjenosti okolja z azbestom pričakujemo porast MM verjetno vsaj do leta 2030. Ob diagnozi ima večina bolnikov z MM že napredovano bolezen, zato je povprečno preživetje kratko in znaša kljub multimodalnemu zdravljenju 14 mesecev. Zaradi naraščajoče incidence in slabe prognoze potrebujemo nove pristope za zgodnejše odkrivanje in s tem učinkovitejše zdravljenje bolnikov z MM, še zlasti pri osebah, ki imajo zaradi izpostavljenosti azbestu visoko tveganje za MM.

Cilji naše raziskave so:

• raziskati možne serumske (topne in eksosomske), genetske (SNP) in epigenetske (miRNA) označevalce pri osebah poklicno izpostavljenih azbestu in pri bolnikih z MM, da bi odkrili nove potencialne biološke označevalce povezane z razvojem azbestnih bolezni in MM, z napredovanjem bolezni, odgovorom na zdravljenje in preživetjem bolnikov z MM

• raziskati vpliv interakcij med različnimi serumskimi, genetskimi, epigenetskimi in okoljskimi dejavniki (izpostavljenost azbestu, kajenje) na tveganje za azbestne bolezni ter na napredovanje bolezni, odgovor na zdravljenje in preživetje bolnikov z MM

• izdelati in validirati multivariatne napovedne modele, ki bodo vključevali klinične in biološke označevalce in bodo temelj za algoritme odločanja, uporabne v klinični praksi.

BRIEF DESCRIPTION OF THE PROJECT

Asbestos related diseases still present a major problem in Slovenia as well as in the world. Asbestos exposure has been associated with the development of asbestosis, pleural plaques, diffuse pleural thickening and pleural effusion, and several types of cancer. One of the most aggressive and fatal cancers associated with asbestos exposure is malignant mesothelioma (MM). Asbestos was banned by law in Slovenia in 1996, but the number of new cases of MM is expected to increase at least until 2030 due to the long latency period and the fact that asbestos is still present in the environment. As most patients present with advanced disease at the time of diagnosis, the average survival time is 14 months with multimodal treatment. Despite improved survival, response rates to chemotherapy are still only up to 40%. The increasing incidence and poor prognosis of MM calls for new more effective detection methods, including the identification of novel biomarkers for early and reliable detection of MM, especially in high-risk populations with a known history of asbestos exposure.

The aims of our study are:

• to investigate potential serum, genetic and epigenetic biomarkers in individuals occupational exposed to asbestos and in MM patients to identify new potential biomarkers for developing asbestos related diseases and MM , for disease progression, treatment response and survival in MM;

• to investigate the influence of interactions between different serum, genetic, epigenetic and environmental factors (asbestos exposure, smoking) on the risk for asbestos related diseases and MM, disease progression, treatment response and survival in MM patients;

• to build and validate multivariate predictive models integrating the clinical and biomarker data into scoring system based decision algorithms that could be used in the clinical practice.

FINANCIRANJE / FINANCING

ARRS

Salonit Anhovo

Veda 3.04 Medicinske vede / Onkologija

Research activity 3.04 Medical sciences / Oncology

Letni obseg / Range on year 0,79

ČLANI PROJEKTNE SKUPINE / PROJECT MEMBERS

SICRIS

Sodelujoče inštitucije / Research Organisations

Univerza v Ljubljani, Medicinska fakulteta

Onkološki Inštitut Ljubljana

Univerzitetni klinični center Ljubljana, Klinični inštitut za medicino dela, prometa in športa

Vodja / Head (SICRIS)

prof. dr. Vita Dolžan, dr. med.

Člani / Researchers (SICRIS)

mag. Niko Arnerić, univ. dipl. psih.

izr. prof. dr. Metoda Dodič-Fikfak, dr. med.

izr. prof. dr. Alenka Franko, dr. med.

doc. dr. Katja Goričar, univ. dipl. biokem.

doc. dr. Viljem Kovač, dr. med.

doc. dr. Metka Lenassi, univ. dipl. mikrobiol.

mag. Barbara Možina, mag. farm., spec. med. biokem.

Pia Pužar Dominkuš, univ. dipl. biokem.

dr. Uroš Smrdel, dr. med.

Danijela Štrbac, dr. med.

FAZE PROJEKTA

01. 05. 2017 – 30. 04. 2020

Meseci 1–12

• zbiranje vzorcev in kliničnih podatkov

• izolacija DNA in genotipizacija, priprava klinično-farmakogenetskih modelov

• optimizacija protokolov za analize plazemskih vzorcev

• statistična analiza podatkov

Meseci 12–24

• nadaljevanje zbiranja vzorcev in kliničnih podatkov

• analiza interakcij

• analize ELISA za mezotelin na eksosomih in v plazmi

• analize na eksosomih

Meseci 24–36

• analize miRNA

• zaključne statistične analize podatkov

• translacija v klinično prakso

PROJECT PHASES

01. 05. 2017 – 30. 04. 2020

Months 1–12

• collection of samples and clinical data

• DNA isolation and genotyping, preparation of clinical-pharmacogenetic models

• optimization of protocols for analysis of plasma samples

• statistical analysis

Months 12–24

• continued collection of samples and clinical data

• analyses of interactions

• mesothelin ELISA analyses in exosomes and plasma

• exosome analyses

Months 24–36

• miRNA analyses

• final statistical analysis

• translation to clinical practice

REFERENCE / REFERENCES

SICRIS

GORIČAR, Katja, KOVAČ, Viljem, DOLŽAN, Vita. Clinical-pharmacogenetic models for personalized cancer treatment : application to malignant mesothelioma. Scientific reports, 2017, vol. 7, 1-9, doi: 10.1038/srep46537. [COBISS.SI-ID 2641275]

ŠTRBAC, Danijela, GORIČAR, Katja, DOLŽAN, Vita, KOVAČ, Viljem. Matrix metalloproteinases polymorphisms as prognostic biomarkers in malignant pleural mesothelioma. Disease markers, 2017, vol. 2017, 1-8, doi: 10.1155/2017/8069529. [COBISS.SI-ID 2743675]

FRANKO, Alenka, KOTNIK, Nika, GORIČAR, Katja, KOVAČ, Viljem, DODIČ-FIKFAK, Metoda, DOLŽAN, Vita. The influence of genetic variability on the risk of developing malignant mesothelioma. Radiology and oncology, 2018, vol. 52, 105-111, doi: 10.1515/raon-2018-0004. [COBISS.SI-ID 2854779]

ŠTRBAC, Danijela, GORIČAR, Katja, DOLŽAN, Vita, KOVAČ, Viljem. Matrix metalloproteinases polymorphisms as baseline risk predictors in malignant pleural mesothelioma. Radiology and oncology, 2018, vol. 52, 160-166, doi: 10.1515/raon-2018-0005. [COBISS.SI-ID 2840955]