Biološki označevalci nastanka, napredovanja in odgovora na zdravljene bolezni povezanih z izpostavljenostjo azbestu
Biological markers of development, progression and treatment response in asbestos related diseases
OPIS PROJEKTA
Dolga latentna doba od izpostavljenosti azbestu do razvoja azbestnih bolezni, vse večja pojavnost malignega mezotelioma (MM) in slaba prognoza kljub multimodalnemu zdravljenju zahteva odkrivanje novih neinvazivnih molekularnih napovednih faktorjev za pravočasno diagnozo in zgodnjo napoved odziva na zdravljenje.
Začrtali smo dve klinični študiji: retrospektivno študijo primerov s kontrolami, ki bo omogočila raziskave novih vrst bioloških označevalcev tveganja za razvoj azbestnih bolezni pri osebah, ki so bile poklicno izpostavljene azbestu, in longitudinalno študijo, ki bo omogočila raziskave odgovora na zdravljenje pri bolnikih z MM. Na genetski ravni bomo preverili, ali genetske spremembe imunskih kontrolnih točk vplivajo na odgovor na zdravljenje MM, in bi jih lahko uporabljali kot neodvisne označevalce, ali pa v kombinaciji z drugimi označevalci. Prav tako bomo raziskali, ali dolžine telomerov in genetski dejavniki, ki bi lahko vplivali na njihovo dolžino, vplivajo na razvoj MM in njegovo agresivnost. Serumski kalretinin je še posebej zanimiv kot potencialni neinvazivni diagnostični ali prognostični označevalec. V tumorskem tkivu kalretinin predstavlja enega najbolj občutljivih in specifičnih imunohistokemijskih označevalcev MM, zadnja poročila pa kažejo, da se njegova raven v krvi lahko poveča več kot eno leto, preden lahko postavimo klinično diagnozo MM. Izmerili bomo raven kalretinina v serumu in raziskali genetske in epigenetske dejavnike, ki uravnavajo njegovo izražanje kot potencialno neodvisne ali sestavljene biomarkerje razvoja, napredovanja in odziva MM.
Najbolj inovativen vidik naše raziskave pa predstavlja preučevanje zunajceličnih veziklov (EV) in njihovega tovora, zlasti miRNA. EV-ji in miRNA so izjemno orodje za preučevanje molekulskih procesov, povezanih z azbestnimi boleznimi, in lahko prispevajo tudi k boljšemu razumevanju osnovnih molekulskih procesov in k prepoznavanju potencialnih tarč, ki omogočajo nove pristope za zdravljenje MM. Na tveganje za nastanek bolezni, povezanih z azbestom, kot tudi na odziv na zdravljenje vplivajo številni dejavniki, katerih vpliv se prepleta, zato je treba pri ocena tveganja upoštevati sočasni vpliv različnih bioloških dejavnikov in njihovo interakcijo z dejavniki okolja in življenjskega sloga. Ob upoštevanju vse večjega števila potencialnih bioloških označevalcev so potrebni multivariatni napovedni modeli za vključitev različnih kliničnih podatkov in bioloških označevalcev v algoritme odločanja, kar bo omogočilo prenos pristopov, ki temeljijo na bioloških označevalcih, v klinično prakso.
Cilji naše raziskave so:
• Identificirati neinvazivne biološke označevalce, ki bi lahko napovedali tveganje za razvoj azbestnih bolezni pri osebah, ki so izpostavljeni azbestu, ter identificirati biološke označevalce za napoved napredovanja bolezni in odziva na zdravljenje pri bolnikih z MM.
• Predpostavljamo, da bi z vključitvijo različnih vrst bioloških označevalcev v multivariatne napovedne modele lahko identificirali nove ali zanesljivejše diagnostične, prognostične in napovedne označevalce MM.
BRIEF DESCRIPTION OF THE PROJECT
The long latency period from asbestos exposure to development of asbestos related diseases, the increasing incidence of malignant mesothelioma (MM) and the poor prognosis despite the multimodal treatment calls for the identification of non-invasive molecular predictors for timely diagnosis and for early prediction of the response to treatment.
We have designed two clinical studies: a retrospective case-control study that will allow the research of a new group of biological markers of development of asbestos related diseases in individuals that were occupationally exposed to asbestos and a longitudinal follow-up study that will allow us to study the biomarkers of treatment response to malignant mesothelioma (MM) treatment with different chemotherapy regimens. On the gene level, we will assess tag SNPs in immune checkpoint genes as potential independent or composite biomarkers of MM treatment response. We will also investigate, if telomere lengths and genetic factors that may influence their length play a role in the development of MM and its aggressiveness. Serum calretinin is such of particular interest as a potential non-invasive diagnostic or prognostic biomarker. In tumor tissue, calretinin represents one of the most sensitive and specific immunohistochemical biomarkers of MM, and recent reports indicate that its blood levels may increase more than one year before the clinical diagnosis of MM can be made. We will measure calretinin serum levels and investigate genetic and epigenetic factors regulating its expression as potential independent or composite biomarkers of MM development, progression and treatment response.
The most innovative aspect of our research, however, is the study of extracellular vesicles (EVs) and their cargo, especially miRNAs. EVs and miRNAs are outstanding tools for studying the molecular processes associated with asbestos-related diseases and can contribute to a better understanding of basic molecular processes and to identification of potential targets enabling new approaches for MM treatment. The risk of developing the asbestos related diseases, as well as the response to treatment, is influenced by many factors whose impact is intertwined, therefor simultaneous impact of different types of biological markers and their interactions with environmental and lifestyle factors must be taken into account in the risk assessment. Taking into account a growing number of potential biomarkers, we will develop multivariate predictive models to integrate the clinical and biomarker data into scoring system based decision algorithms that would enable the translation of biomarker based approaches into clinical practice.
The aims of our study are:
• To identify non-invasive biological markers that may predict the risk for developing asbestos related diseases in asbestos-exposed individuals, as well as to identify biomarkers predictive for disease progression and treatment response in MM patients.
• We hypothesize that by integrating different classes of biomarkers in multivariable predictive models, we would be able to identify novel or more reliable diagnostic, prognostic and predictive biomarkers for MM.
FINANCIRANJE / FINANCING
ARRS
Salonit Anhovo
Veda 3.04 Medicinske vede / Onkologija
Research activity 3.04 Medical sciences / Oncology
